321 results on '"Neuron loss"'
Search Results
2. Epimedium Aqueous Extract Ameliorates Cerebral Ischemia/Reperfusion Injury through Inhibiting ROS/NLRP3-Mediated Pyroptosis.
- Author
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Wu, Xiaoyu, Wei, Jiajia, Yi, Yang, Shu, Guotao, He, Zhixu, Gong, Qihai, and Gao, Jianmei
- Subjects
REPERFUSION injury ,CEREBRAL ischemia ,PYROPTOSIS ,EPIMEDIUM ,BRAIN damage ,CEREBRAL arteries - Abstract
Cerebral ischemia/reperfusion causes exacerbated neuronal damage involving excessive neuroinflammation and oxidative stress. ROS is considered a signal molecule to activate NLRP3; thus, the ROS/NLRP3/pyroptosis axis plays a vital role in the pathogenesis of cerebral ischemia/reperfusion injury (CIRI). Therefore, targeting the inhibition of the ROS/NLRP3/pyroptosis axis may be a promising therapeutic tactic for CIRI. Epimedium (EP) contains many active ingredients (ICA, ICS II, and ICT), which have a wide range of pharmacological activities. However, whether EP can protect against CIRI remains unknown. Thus, in this study, we designed to investigate the effect and possible underlying mechanism of EP on CIRI. The results showed that treatment with EP dramatically mitigated brain damage in rats following CIRI, which was achieved by suppressing mitochondrial oxidative stress and neuroinflammation. Furthermore, we identified the ROS/NLRP3/pyroptosis axis as a vital process and NLRP3 as a vital target in EP-mediated protection. Most interestingly, the main compounds of EP directly bonded with NLRP3, as reflected by molecular docking, which indicated that NLRP3 might be a promising therapeutic target for EP-elicited cerebral protection. In conclusion, our findings illustrate that ICS II protects against neuron loss and neuroinflammation after CIRI by inhibiting ROS/NLRP3-mediated pyroptosis. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
3. Influence of age on the pathology of hippocampus and variation in the number of neurons of the hilar region in the brain of dogs
- Author
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T. Dhanya, K. S. Prasanna, P. Hamza, R. Anoopraj, M. Pradeep, V. Elizabeth, M. T. K. Alin, and J. G. Ajith
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dog ,hippocampus ,age ,neuron loss ,hilus ,Animal biochemistry ,QP501-801 ,Science (General) ,Q1-390 - Abstract
Brain is a vital organ that always has high oxygen demands and is highly vulnerable to injury caused by reactive oxygen species (ROS). The hippocampus is a complex structure seen deep in the temporal lobe which is constituted by the dentate gyrus, hippocampus proper (Cornu Ammonis- CA1-CA4) and subiculum. The important functions of the hippocampus are learning and memory. Age-influenced pathological lesions in the hippocampus and variation in the number of neurons in the hilus are the main discussion of this study. The major gross lesions observed in the brain of both younger and older dogs were cerebral congestion, thickened meninges and cerebral edema. The major histopathological findings in the hippocampus were thickened blood vessels, accumulation of lipofuscin pigments in the neuronal cytoplasm, satellitosis, gliosis, neurons with the vesicular nucleus, chromatolysis and neuronophagia. A statistically significant reduction in the number of neurons in the hilar region of the hippocampus was observed in aged dogs.
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- 2022
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- View/download PDF
4. A Combination of Caffeine Supplementation and Enriched Environment in an Alzheimer's Disease Mouse Model.
- Author
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Stazi, Martina, Zampar, Silvia, Klafki, Hans-Wolfgang, Meyer, Thomas, and Wirths, Oliver
- Subjects
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ALZHEIMER'S disease , *LABORATORY mice , *ANIMAL disease models , *CAFFEINE , *NOOTROPIC agents , *AMYLOID plaque - Abstract
A variety of factors has been associated with healthy brain aging, and epidemiological studies suggest that physical activity and nutritional supplements such as caffeine may reduce the risk of developing dementia and, in particular, Alzheimer's disease (AD) in later life. Caffeine is known to act as a cognitive enhancer but has been also shown to positively affect exercise performance in endurance activities. We have previously observed that chronic oral caffeine supplementation and a treatment paradigm encompassing physical and cognitive stimulation by enriched environment (EE) housing can improve learning and memory performance and ameliorate hippocampal neuron loss in the Tg4-42 mouse model of AD. Here, we investigated whether these effects were synergistic. To that end, previous findings on individual treatments were complemented with unpublished, additional data and analyzed in depth by ANOVA followed by Bonferroni multiple comparison post tests. We further evaluated whether plasma neurofilament light chain levels reflect neuropathological and behavioral changes observed in the experimental groups. While a treatment combining physical activity and caffeine supplementation significantly improved learning and memory function compared to standard-housed vehicle-treated Tg4-42 in tasks such as the Morris water maze, no major additive effect outperforming the effects of the single interventions was observed. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
5. Old-age hippocampal sclerosis in the aged population
- Author
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Hokkanen, Suvi Rosa Kastehelmi, Brayne, Carol, and Polvikoski, Tuomo
- Subjects
618.97 ,neuropathology ,hippocampal sclerosis ,TDP-43 ,population study ,hippocampus ,neuron loss - Abstract
Old-age hippocampal sclerosis (HS), characterised by severe neuron loss in hippocampal CA1, is a poorly understood cause of dementia. At present no objective pathological HS criteria exist. In life HS is commonly diagnosed as Alzheimer's disease. HS aetiology is unclear, although it has been associated with both ischaemia and TAR-DNA-binding protein-43 (TDP-43)-related neurodegeneration. Variations in genes GRN, TMEM106B and ABCC9 are proposed as HS risk factors. The aim of this thesis was to investigate epidemiological, clinical, pathological and genetic characteristics of HS in older European populations. 976 brains donated for the Cambridge City over-75s Cohort, the Cognitive Function and Ageing Study and the Finnish Vantaa 85+ study were available for evaluation -including bilateral hippocampi from 302 individuals. A protocol capturing the extent and severity of hippocampal neuron loss was developed, establishing objective HS diagnosis criteria and allowing observation of distinct neuron loss patterns associated with ischaemia and neurodegeneration. 71 HS cases (overall prevalence: 7.3%) were identified. HS was significantly associated with an advanced age at death as well as dementia at the end of life. Neuropsychological and cardiovascular characteristics were similar between HS and AD, except for a longer duration of dementia and more disability in HS. HS was not associated with neurofibrillary tangles, amyloid plaques, or vascular pathologies, but all HS cases evaluated for TDP-43 showed neuronal inclusions in the hippocampal dentate and a high frequency of other glial, neuronal and neurite TDP-43 pathologies. GRN and TMEM106B but not ABCC9 variations were linked to HS. A moderating effect of TDP-43 on this association was detected. HS presented pathologically similarly to frontotemporal dementia cases with TDP-43 (FTLD-TDP) caused by mutations in GRN, but differed from other FTLD-TDP subtypes. Results of this thesis reveal the importance of HS in the oldest old in the population, the key role of TDP-43, as well as providing robust methods to capture HS characteristics for an area that has been under-researched but is clearly vital to understanding dementia in the oldest old.
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- 2018
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6. DNA vaccines targeting amyloid-β oligomer ameliorate cognitive deficits of aged APP/PS1/tau triple-transgenic mouse models of Alzheimer’s disease
- Author
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Sha Sha, Xiao-Na Xing, Tao Wang, Ying Li, Rong-Wei Zhang, Xue-Li Shen, Yun-Peng Cao, and Le Qu
- Subjects
aβ oligomers ,cognitive dysfunction ,dna vaccine ,immunotherapy ,neuron loss ,plaque deposits ,synaptic function ,tau hyperphosphorylation ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
The amyloid-β (Aβ) oligomer, rather than the Aβ monomer, is considered to be the primary initiator of Alzheimer’s disease. It was hypothesized that p(Aβ3–10)10-MT, the recombinant Aβ3–10 gene vaccine of the Aβ oligomer has the potential to treat Alzheimer’s disease. In this study, we intramuscularly injected the p(Aβ3–10)10-MT vaccine into the left hindlimb of APP/PS1/tau triple-transgenic mice, which are a model for Alzheimer’s disease. Our results showed that the p(Aβ3–10)10-MT vaccine effectively reduced Aβ oligomer levels and plaque deposition in the cerebral cortex and hippocampus, decreased the levels tau protein variants, reduced synaptic loss, protected synaptic function, reduced neuron loss, and ameliorated memory impairment without causing any cerebral hemorrhaging. Therefore, this novel DNA vaccine, which is safe and highly effective in mouse models of Alzheimer’s disease, holds a lot of promise for the treatment of Alzheimer’s disease in humans.
- Published
- 2022
- Full Text
- View/download PDF
7. The association between neurodegeneration and local complement activation in the thalamus to progressive multiple sclerosis outcome.
- Author
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Cooze, Benjamin J., Dickerson, Matthew, Loganathan, Rukshikah, Watkins, Lewis M., Grounds, Ethan, Pearson, Ben R., Bevan, Ryan Jack, Morgan, B. Paul, Magliozzi, Roberta, Reynolds, Richard, Neal, James W., and Howell, Owain W.
- Subjects
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COMPLEMENT activation , *THALAMIC nuclei , *THALAMUS , *MULTIPLE sclerosis , *WHITE matter (Nerve tissue) , *DISEASE duration - Abstract
The extent of grey matter demyelination and neurodegeneration in the progressive multiple sclerosis (PMS) brains at post‐mortem associates with more severe disease. Regional tissue atrophy, especially affecting the cortical and deep grey matter, including the thalamus, is prognostic for poor outcomes. Microglial and complement activation are important in the pathogenesis and contribute to damaging processes that underlie tissue atrophy in PMS. We investigated the extent of pathology and innate immune activation in the thalamus in comparison to cortical grey and white matter in blocks from 21 cases of PMS and 10 matched controls. Using a digital pathology workflow, we show that the thalamus is invariably affected by demyelination and had a far higher proportion of active inflammatory lesions than forebrain cortical tissue blocks from the same cases. Lesions were larger and more frequent in the medial nuclei near the ventricular margin, whilst neuronal loss was greatest in the lateral thalamic nuclei. The extent of thalamic neuron loss was not associated with thalamic demyelination but correlated with the burden of white matter pathology in other forebrain areas (Spearman r = 0.79, p < 0.0001). Only thalamic neuronal loss, and not that seen in other forebrain cortical areas, correlated with disease duration (Spearman r = −0.58, p = 0.009) and age of death (Spearman r = −0.47, p = 0.045). Immunoreactivity for the complement pattern recognition molecule C1q, and products of complement activation (C4d, Bb and C3b) were elevated in thalamic lesions with an active inflammatory pathology. Complement regulatory protein, C1 inhibitor, was unchanged in expression. We conclude that active inflammatory demyelination, neuronal loss and local complement synthesis and activation in the thalamus, are important to the pathological and clinical disease outcomes of PMS. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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8. High frequency repetitive transcranial magnetic stimulation alleviates cognitive deficits in 3xTg-AD mice by modulating the PI3K/Akt/GLT-1 axis
- Author
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Huan Cao, Chengchao Zuo, Zhongya Gu, Yaqi Huang, Yuyan Yang, Liudi Zhu, Yongsheng Jiang, and Furong Wang
- Subjects
Alzheimer's disease ,rTMS ,Oxidative stress ,Neuroinflammation ,Synaptic plasticity ,Neuron loss ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Objective: Glutamate mediated excitotoxicity, such as oxidative stress, neuroinflammation, synaptic loss and neuronal death, is ubiquitous in Alzheimer's disease (AD). Our previous study found that 15 Hz repetitive transcranial magnetic stimulation (rTMS) could reduce cortical excitability. The purpose of this study was to explore the therapeutic effect of higher frequency rTMS on 3xTg-AD model mice and further explore the mechanisms of rTMS. Methods: First, WT and 3xTg-AD model mice received 25 Hz rTMS treatment for 21 days. The Morris water maze test was used to evaluate the cognitive function. The levels of Aβ and neuroinflammation were assessed by ELISA and immunofluorescence. Oxidative stress was quantified by biochemical assay kits. Brain glucose metabolism was assessed by 18F-FDG PET. Apoptosis was assessed by western blot and TUNEL staining. Synaptic plasticity and PI3K/Akt/GLT-1 pathway related protein expression were assessed by western blot. Next, to explore the activity of PI3K/Akt in the therapeutic effect of rTMS, 3xTg-AD model mice were given LY294002 intervention and rTMS treatment for 21 days, the experimental method was the same as before. Results: We found that 25 Hz rTMS could improve cognitive function of 3xTg-AD model mice, reduce hippocampal Aβ1-42 levels, ameliorate oxidative stress and improve glucose metabolism. rTMS alleviated neuroinflammatory response, enhanced synaptic plasticity and reduced neuronal loss and cell apoptosis, accompanied by activation of PI3K/Akt/GLT-1 pathway. After administration of PI3K/Akt inhibitor LY294002, 25 Hz rTMS could not improve the cognitive function and reduce neuron damage of 3xTg-AD model mice, nor could it upregulate the expression of GLT-1, indicating that its therapeutic and protective effects required the involvement of PI3K/Akt/GLT-1 pathway. Conclusion: rTMS exerts protective role for AD through regulating multiple pathological processes. Meanwhile, this study revealed the key role of PI3K/Akt/GLT-1 pathway in the treatment of AD by rTMS, which might be a new target.
- Published
- 2022
- Full Text
- View/download PDF
9. Epimedium Aqueous Extract Ameliorates Cerebral Ischemia/Reperfusion Injury through Inhibiting ROS/NLRP3-Mediated Pyroptosis
- Author
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Xiaoyu Wu, Jiajia Wei, Yang Yi, Guotao Shu, Zhixu He, Qihai Gong, and Jianmei Gao
- Subjects
Epimedium ,cerebral ischemic/reperfusion injury ,neuron loss ,neuroinflammation ,NLRP3 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Cerebral ischemia/reperfusion causes exacerbated neuronal damage involving excessive neuroinflammation and oxidative stress. ROS is considered a signal molecule to activate NLRP3; thus, the ROS/NLRP3/pyroptosis axis plays a vital role in the pathogenesis of cerebral ischemia/reperfusion injury (CIRI). Therefore, targeting the inhibition of the ROS/NLRP3/pyroptosis axis may be a promising therapeutic tactic for CIRI. Epimedium (EP) contains many active ingredients (ICA, ICS II, and ICT), which have a wide range of pharmacological activities. However, whether EP can protect against CIRI remains unknown. Thus, in this study, we designed to investigate the effect and possible underlying mechanism of EP on CIRI. The results showed that treatment with EP dramatically mitigated brain damage in rats following CIRI, which was achieved by suppressing mitochondrial oxidative stress and neuroinflammation. Furthermore, we identified the ROS/NLRP3/pyroptosis axis as a vital process and NLRP3 as a vital target in EP-mediated protection. Most interestingly, the main compounds of EP directly bonded with NLRP3, as reflected by molecular docking, which indicated that NLRP3 might be a promising therapeutic target for EP-elicited cerebral protection. In conclusion, our findings illustrate that ICS II protects against neuron loss and neuroinflammation after CIRI by inhibiting ROS/NLRP3-mediated pyroptosis.
- Published
- 2023
- Full Text
- View/download PDF
10. Droplet Degeneration of Hippocampal and Cortical Neurons Signifies the Beginning of Neuritic Plaque Formation.
- Author
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Streit, Wolfgang J., Rotter, Jonas, Winter, Karsten, Müller, Wolf, Khoshbouei, Habibeh, and Bechmann, Ingo
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AMYLOID plaque , *NEURONS , *SOCIAL degeneration , *IRON , *NEUROFIBRILLARY tangles , *HIPPOCAMPUS (Brain) - Abstract
Background: Neuritic plaques contain neural and microglial elements, and amyloid-β protein (Aβ), but their pathogenesis remains unknown.Objective: Elucidate neuritic plaque pathogenesis.Methods: Histochemical visualization of hyperphosphorylated-tau positive (p-tau+) structures, microglia, Aβ, and iron.Results: Disintegration of large projection neurons in human hippocampus and neocortex presents as droplet degeneration: pretangle neurons break up into spheres of numerous p-tau+ droplets of various sizes, which marks the beginning of neuritic plaques. These droplet spheres develop in the absence of colocalized Aβ deposits but once formed become encased in diffuse Aβ with great specificity. In contrast, neurofibrillary tangles often do not colocalize with Aβ. Double-labelling for p-tau and microglia showed a lack of microglial activation or phagocytosis of p-tau+ degeneration droplets but revealed massive upregulation of ferritin in microglia suggesting presence of high levels of free iron. Perl's Prussian blue produced positive staining of microglia, droplet spheres, and Aβ plaque cores supporting the suggestion that droplet degeneration of pretangle neurons in the hippocampus and cortex represents ferroptosis, which is accompanied by the release of neuronal iron extracellularly.Conclusion: Age-related iron accumulation and ferroptosis in the CNS likely trigger at least two endogenous mechanisms of neuroprotective iron sequestration and chelation, microglial ferritin expression and Aβ deposition, respectively, both contributing to the formation of neuritic plaques. Since neurofibrillary tangles and Aβ deposits colocalize infrequently, tangle formation likely does not involve release of neuronal iron extracellularly. In human brain, targeted deposition of Aβ occurs specifically in response to ongoing ferroptotic droplet degeneration thereby producing neuritic plaques. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
11. Combined treatment with valproic acid and estrogen has neuroprotective effects in ovariectomized mice with Alzheimer’s disease
- Author
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Yan-Zhen Li, Yuan-Jie Liu, Wei Zhang, Shi-Fang Luo, Xin Zhou, and Gui-Qiong He
- Subjects
17β-estradiol ,amyloid β ,dementia ,estrogen receptor α ,estrogen receptor β ,glycogen synthase kinase-3β ,liquiritigenin ,menopause ,neuron loss ,tau ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Postmenopausal women with Alzheimer’s disease (AD) exhibit dramatically reduced sensitivity to estrogen replacement therapy, which is though to be related to an estrogen receptor (ER)α/ERβ ratio imbalance arising from a significantly decreased level of ERs of the brain. The aim of our study was to investigate whether valproic acid (VPA) can enhance the beneficial effects of estrogen on cognitive function through restoration of ERα and ERβ expression in the brain. We removed the ovaries of female APP/PS1 mice to simulate the low estrogen levels present in postmenopausal women and then administered VPA (30 mg/kg, intraperitoneal injection, once daily), 17β-estradiol (E2) (2.4 μg, intraperitoneal injection, once daily), liquiritigenin (LG) (50 μg/kg, intragastric infusion, once daily), VPA + E2, or VPA + LG for 4 successive weeks. Compared with treatment with a single drug, treatment with VPA + E2 or VPA + LG significantly increased the level of glycogen synthase kinase 3β, increased the expression of estrogen receptor α, reduced the expression of small ubiquitin-like modifiers, and increased the level of estrogen receptor β. This resulted in enhanced sensitivity to estrogen therapy, reduced amyloid β aggregation, reduced abnormal phosphorylation of the tau protein, reduced neuronal loss, increased dendritic spine and postsynaptic density, and significantly alleviated memory loss and learning impairment in mice. This study was approved by the Chongqing Medical University Animal Protection and Ethics Committee, China on March 6, 2013.
- Published
- 2021
- Full Text
- View/download PDF
12. Cerebrospinal fluid proteomics reveal potential protein targets of JiaWeiSiNiSan in preventing chronic psychological stress damage
- Author
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Han-Zhang Wang, Wu-Long Luo, Ning-Xi Zeng, Hui-Zhen Li, Ling Li, Can Yan, and Li-Li Wu
- Subjects
stress resilience ,hippocampus neurogenesis ,neuron loss ,chronic unpredictable mild stress model ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Context Chinese herbal formula JiaWeiSiNiSan (JWSNS) has been widely used to prevent stress-induced neuropsychiatric ailments in clinics and proven to have therapeutic anti-stress effects on rats. However, the mechanism remains unclear. Objective Based on the proteomics of cerebrospinal fluid (CSF), this study explores the possible mechanism and target proteins of JiaWeiSiNiSan raising stress resilience and preventing stress damage. Materials and methods A 6-week Chronic Unpredictable Mild Stress (CUMS) model was applied on adult Wistar male rats to observe the effects of JWSNS on improving mental stress resilience. Tandem Mass Tag (TMT) proteomics and bioinformatics analysis were used to screen and analyze differentially expressed proteins (DEPs) in CSF. Parallel Reaction Monitoring (PRM) was used to validate target DEPs. Results Significantly decreased sucrose preference, locomotion activity level and accuracy of T-maze, as well as increased immobility time, were observed in CUMS rats compared to CON rats while JWSNS improved above depression-like behaviours. The quantitative proteomics and bioinformatics analysis showed that JWSNS decreased the expression of Rps4x, HSP90AA1, Rps12, Uba1, Rsp14, Tuba1b in CUMS rats CSF (p
- Published
- 2021
- Full Text
- View/download PDF
13. Cerebrospinal fluid proteomics reveal potential protein targets of JiaWeiSiNiSan in preventing chronic psychological stress damage.
- Author
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Wang, Han-Zhang, Luo, Wu-Long, Zeng, Ning-Xi, Li, Hui-Zhen, Li, Ling, Yan, Can, and Wu, Li-Li
- Subjects
- *
CEREBROSPINAL fluid , *PSYCHOLOGICAL stress , *PROTEOMICS , *DENTATE gyrus , *CEREBROSPINAL fluid examination - Abstract
Chinese herbal formula JiaWeiSiNiSan (JWSNS) has been widely used to prevent stress-induced neuropsychiatric ailments in clinics and proven to have therapeutic anti-stress effects on rats. However, the mechanism remains unclear. Based on the proteomics of cerebrospinal fluid (CSF), this study explores the possible mechanism and target proteins of JiaWeiSiNiSan raising stress resilience and preventing stress damage. A 6-week Chronic Unpredictable Mild Stress (CUMS) model was applied on adult Wistar male rats to observe the effects of JWSNS on improving mental stress resilience. Tandem Mass Tag (TMT) proteomics and bioinformatics analysis were used to screen and analyze differentially expressed proteins (DEPs) in CSF. Parallel Reaction Monitoring (PRM) was used to validate target DEPs. Significantly decreased sucrose preference, locomotion activity level and accuracy of T-maze, as well as increased immobility time, were observed in CUMS rats compared to CON rats while JWSNS improved above depression-like behaviours. The quantitative proteomics and bioinformatics analysis showed that JWSNS decreased the expression of Rps4x, HSP90AA1, Rps12, Uba1, Rsp14, Tuba1b in CUMS rats CSF (p < 0.05, FDR < 0.5). Immunofluorescence results showed that the number of BrdU/DCX positive cells (p < 0.01) and the relative number of neurons (p < 0.01) in the hippocampus dentate gyrus (DG) of the JSWNS group significantly increased, compared with the CUMS group. JWSNS could increase mental stress resilience and prevent stress damage by regulating proteins in CSF. This study provides a scientific basis for further study on Chinese formulas preventing mental illness. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
14. A novel and accurate full-length HTT mouse model for Huntington’s disease
- Author
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Sushila A Shenoy, Sushuang Zheng, Wencheng Liu, Yuanyi Dai, Yuanxiu Liu, Zhipeng Hou, Susumu Mori, Yi Tang, Jerry Cheng, Wenzhen Duan, and Chenjian Li
- Subjects
huntington's disease ,neurodegeneration ,transgenic mouse ,brain atrophy ,neuron loss ,Htt aggregates ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Here, we report the generation and characterization of a novel Huntington’s disease (HD) mouse model BAC226Q by using a bacterial artificial chromosome (BAC) system, expressing full-length human HTT with ~226 CAG-CAA repeats and containing endogenous human HTT promoter and regulatory elements. BAC226Q recapitulated a full-spectrum of age-dependent and progressive HD-like phenotypes without unwanted and erroneous phenotypes. BAC226Q mice developed normally, and gradually exhibited HD-like psychiatric and cognitive phenotypes at 2 months. From 3 to 4 months, BAC226Q mice showed robust progressive motor deficits. At 11 months, BAC226Q mice showed significant reduced life span, gradual weight loss and exhibited neuropathology including significant brain atrophy specific to striatum and cortex, striatal neuronal death, widespread huntingtin inclusions, and reactive pathology. Therefore, the novel BAC226Q mouse accurately recapitulating robust, age-dependent, progressive HD-like phenotypes will be a valuable tool for studying disease mechanisms, identifying biomarkers, and testing gene-targeting therapeutic approaches for HD.
- Published
- 2022
- Full Text
- View/download PDF
15. A Combination of Caffeine Supplementation and Enriched Environment in an Alzheimer’s Disease Mouse Model
- Author
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Martina Stazi, Silvia Zampar, Hans-Wolfgang Klafki, Thomas Meyer, and Oliver Wirths
- Subjects
Alzheimer’ disease ,amyloid-β ,caffeine ,physical activity ,behavior ,neuron loss ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
A variety of factors has been associated with healthy brain aging, and epidemiological studies suggest that physical activity and nutritional supplements such as caffeine may reduce the risk of developing dementia and, in particular, Alzheimer’s disease (AD) in later life. Caffeine is known to act as a cognitive enhancer but has been also shown to positively affect exercise performance in endurance activities. We have previously observed that chronic oral caffeine supplementation and a treatment paradigm encompassing physical and cognitive stimulation by enriched environment (EE) housing can improve learning and memory performance and ameliorate hippocampal neuron loss in the Tg4-42 mouse model of AD. Here, we investigated whether these effects were synergistic. To that end, previous findings on individual treatments were complemented with unpublished, additional data and analyzed in depth by ANOVA followed by Bonferroni multiple comparison post tests. We further evaluated whether plasma neurofilament light chain levels reflect neuropathological and behavioral changes observed in the experimental groups. While a treatment combining physical activity and caffeine supplementation significantly improved learning and memory function compared to standard-housed vehicle-treated Tg4-42 in tasks such as the Morris water maze, no major additive effect outperforming the effects of the single interventions was observed.
- Published
- 2023
- Full Text
- View/download PDF
16. N-Truncated Aβ Starting at Position Four—Biochemical Features, Preclinical Models, and Potential as Drug Target in Alzheimer's Disease.
- Author
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Bayer, Thomas A.
- Subjects
DRUG target ,ALZHEIMER'S disease ,ANIMAL models in research ,DRUG toxicity ,AMYLOID plaque ,DRUG development - Abstract
The discussion of whether amyloid plaque Aβ is a valid drug target to fight Alzheimer's disease (AD) has been a matter of scientific dispute for decades. This question can only be settled by successful clinical trials and the approval of disease-modifying drugs. However, many clinical trials with antibodies against different regions of the amyloid Aβ peptide have been discontinued, as they did not meet the clinical endpoints required. Recently, passive immunization of AD patients with Donanemab, an antibody directed against the N-terminus of pyroglutamate Aβ, showed beneficial effects in a phase II trial, supporting the concept that N-truncated Aβ is a relevant target for AD therapy. There is long-standing evidence that N-truncated Aβ variants are the main variants found in amyloid plaques besides full-length Aβ
1–42 , t, therefore their role in triggering AD pathology and as targets for drug development are of interest. While the contribution of pyroglutamate Aβ3–42 to AD pathology has been well studied in the past, the potential role of Aβ4–42 has been largely neglected. The present review will therefore focus on Aβ4–42 as a possible drug target based on human and mouse pathology, in vitro and in vivo toxicity, and anti-Aβ4-X therapeutic effects in preclinical models. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
17. N-Truncated Aβ Starting at Position Four—Biochemical Features, Preclinical Models, and Potential as Drug Target in Alzheimer’s Disease
- Author
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Thomas A. Bayer
- Subjects
N-truncated Aβ ,Tg4–42 ,transgenic mouse model ,immunotherapy ,neuron loss ,PET ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The discussion of whether amyloid plaque Aβ is a valid drug target to fight Alzheimer’s disease (AD) has been a matter of scientific dispute for decades. This question can only be settled by successful clinical trials and the approval of disease-modifying drugs. However, many clinical trials with antibodies against different regions of the amyloid Aβ peptide have been discontinued, as they did not meet the clinical endpoints required. Recently, passive immunization of AD patients with Donanemab, an antibody directed against the N-terminus of pyroglutamate Aβ, showed beneficial effects in a phase II trial, supporting the concept that N-truncated Aβ is a relevant target for AD therapy. There is long-standing evidence that N-truncated Aβ variants are the main variants found in amyloid plaques besides full-length Aβ1–42, t, therefore their role in triggering AD pathology and as targets for drug development are of interest. While the contribution of pyroglutamate Aβ3–42 to AD pathology has been well studied in the past, the potential role of Aβ4–42 has been largely neglected. The present review will therefore focus on Aβ4–42 as a possible drug target based on human and mouse pathology, in vitro and in vivo toxicity, and anti-Aβ4-X therapeutic effects in preclinical models.
- Published
- 2021
- Full Text
- View/download PDF
18. Aging in the Canine and Feline Brain
- Author
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Vite, Charles H and Head, Elizabeth
- Subjects
Orphan Drug ,Neurosciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Dementia ,Alzheimer's Disease ,Neurodegenerative ,Acquired Cognitive Impairment ,Aging ,Rare Diseases ,Brain Disorders ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Animals ,Brain Diseases ,Cat Diseases ,Cats ,Dog Diseases ,Dogs ,Cat ,Cognitive dysfunction ,Dog ,Neuron loss ,Tau ,β-Amyloid ,Veterinary Sciences - Abstract
Aging dogs and cats show neurodegenerative features that are similar to human aging and Alzheimer disease. Neuropathologic changes with age may be linked to signs of cognitive dysfunction both in the laboratory and in a clinic setting. Less is known about cat brain aging and cognition and this represents an area for further study. Neurodegenerative diseases such as lysosomal storage diseases in dogs and cats also show similar features of human aging, suggesting some common underlying pathogenic mechanisms and also suggesting pathways that can be modified to promote healthy brain aging.
- Published
- 2014
19. Neuronal loss and microgliosis are restricted to the core of Aβ deposits in mouse models of Alzheimer's disease.
- Author
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Zhang, Jing, Wu, Na, Wang, Shubo, Yao, Zitong, Xiao, Fuchuan, Lu, Jing, and Chen, Baian
- Subjects
- *
LABORATORY mice , *ALZHEIMER'S disease , *MYELIN sheath , *NEUROFIBRILLARY tangles , *MYELIN proteins , *NEUROINFLAMMATION , *AXONS - Abstract
Amyloid‐β (Aβ) deposits, pathologic tau, and neurodegeneration are major pathological hallmarks of Alzheimer's disease (AD). The relationship between neuronal loss and Aβ deposits is one of the fundamental questions in the pathogenesis of AD. However, this relationship is controversial. One main reason for the conflicting results may be the confounding effects of pathologic tau, which often coexists with Aβ deposits in the brains of AD patients. To clarify the relationship between neuronal loss and Aβ deposits, mouse models of AD, which develop abundant Aβ deposits in the aged brain without pathologic tau, were used to examine the co‐localization of NeuN‐positive neurons, NF‐H‐positive axons, MBP‐positive myelin sheaths, and Aβ deposits. Neuronal loss, as measured by decreased staining of the neuronal cell body, axon, and myelin sheath, as well as the IBA‐1‐positive microglia, was significantly increased in the core area of cerebral Aβ deposits, but not in adjacent areas. Furthermore, neuronal loss in the core area of cerebral Aβ deposits was correlated with Aβ deposit size. These results clearly indicate that neuronal loss is restricted to the core of Aβ deposits, and this restricted loss probably occurs because the Aβ deposit attracts microglia, which cluster in the core area where Aβ toxicity and neuroinflammation toxicity are restrained. These findings may contribute to our understanding of the relationship between neuronal loss and Aβ deposits in the absence of pathologic tau. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
20. Chronic Memantine Treatment Ameliorates Behavioral Deficits, Neuron Loss, and Impaired Neurogenesis in a Model of Alzheimer's Disease.
- Author
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Stazi, Martina and Wirths, Oliver
- Abstract
Memantine, a non-competitive NMDA receptor antagonist possessing neuroprotective properties, belongs to the small group of drugs which have been approved for the treatment of Alzheimer's disease (AD). While several preclinical studies employing different transgenic AD mouse models have described beneficial effects with regard to rescued behavioral deficits or reduced amyloid plaque pathology, it is largely unknown whether memantine might have beneficial effects on neurodegeneration. In the current study, we assessed whether memantine treatment has an impact on hippocampal neuron loss and associated behavioral deficits in the Tg4-42 mouse model of AD. We demonstrate that a chronic oral memantine treatment for 4 months diminishes hippocampal CA1 neuron loss and rescues learning and memory performance in different behavioral paradigms, such as Morris water maze or a novel object recognition task. Cognitive benefits of chronic memantine treatment were accompanied by an amelioration of impaired adult hippocampal neurogenesis. Taken together, our results demonstrate that memantine successfully counteracts pathological alterations in a preclinical mouse model of AD. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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21. STAT3 ameliorates truncated tau-induced cognitive deficits.
- Author
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Zhang B, Wan H, Maierwufu M, Liu Q, Li T, He Y, Wang X, Liu G, Hong X, and Feng Q
- Abstract
Proteolytic cleavage of tau by asparagine endopeptidase (AEP) creates tau-N368 fragments, which may drive the pathophysiology associated with synaptic dysfunction and memory deterioration in the brain of Alzheimer's disease patients. Nonetheless, the molecular mechanisms of truncated tau-induced cognitive deficits remain unclear. Evidence suggests that signal transduction and activator of transcription-3 (STAT3) is associated with modulating synaptic plasticity, cell apoptosis, and cognitive function. Using luciferase reporter assays, electrophoretic mobility shift assays, western blotting, and immunofluorescence, we found that human tau-N368 accumulation inhibited STAT3 activity by suppressing STAT3 translocation into the nucleus. Overexpression of STAT3 improved tau-N368-induced synaptic deficits and reduced neuronal loss, thereby improving the cognitive deficits in tau-N368 mice. Moreover, in tau-N368 mice, activation of STAT3 increased N-methyl-D-aspartic acid receptor levels, decreased Bcl-2 levels, reversed synaptic damage and neuronal loss, and thereby alleviated cognitive deficits caused by tau-N368. Taken together, STAT3 plays a critical role in truncated tau-related neuropathological changes. This indicates a new mechanism behind the effect of tau-N368 on synapses and memory deficits. STAT3 can be used as a new molecular target to treat tau-N368-induced protein pathology., Competing Interests: None
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- 2024
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22. Texture Features of Magnetic Resonance Images: an Early Marker of Post-stroke Cognitive Impairment.
- Author
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Betrouni, Nacim, Yasmina, Moussaoui, Bombois, Stéphanie, Pétrault, Maud, Dondaine, Thibaut, Lachaud, Cédrick, Laloux, Charlotte, Mendyk, Anne-Marie, Henon, Hilde, and Bordet, Régis
- Abstract
Stroke is frequently associated with delayed, long-term cognitive impairment (CI) and dementia. Recent research has focused on identifying early predictive markers of CI occurrence. We carried out a texture analysis of magnetic resonance (MR) images to identify predictive markers of CI occurrence based on a combination of preclinical and clinical data. Seventy-two-hour post-stroke T1W MR images of 160 consecutive patients were examined, including 75 patients with confirmed CI at the 6-month post-stroke neuropsychological examination. Texture features were measured in the hippocampus and entorhinal cortex and compared between patients with CI and those without. A correlation study determined their association with MoCA and MMSE clinical scores. Significant features were then combined with the classical prognostic factors, age and gender, to build a machine learning algorithm as a predictive model for CI occurrence. A middle cerebral artery transient occlusion model was used. Texture features were compared in the hippocampus of sham and lesioned rats and were correlated with histologically assessed neural loss. In clinical studies, two texture features, kurtosis and inverse difference moment, differed significantly between patients with and without CI and were significantly correlated with MoCA and MMSE scores. The prediction model had an accuracy of 88 ± 3%. The preclinical model revealed a significant correlation between texture features and neural density in the hippocampus contralateral to the ischemic area. These preliminary results suggest that texture features of MR images are representative of neural alteration and could be a part of a screening strategy for the early prediction of post-stroke CI. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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23. Toxic Tau Aggregation in AD
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Takashima, Akihiko, Cohen, Irun R., Series editor, Lajtha, N.S. Abel, Series editor, Paoletti, Rodolfo, Series editor, Lambris, John D., Series editor, Vlamos, Panayiotis, editor, and Alexiou, Athanasios, editor
- Published
- 2015
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24. Characterization of a Mouse Model of Alzheimer’s Disease Expressing Aβ4-42 and Human Mutant Tau
- Author
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Silvia Zampar and Oliver Wirths
- Subjects
Alzheimer’ disease ,amyloid β ,tau ,behavior ,neuron loss ,transgenic mice ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The relationship between the two most prominent neuropathological hallmarks of Alzheimer’s Disease (AD), extracellular amyloid-β (Aβ) deposits and intracellular accumulation of hyperphosphorylated tau in neurofibrillary tangles (NFT), remains at present not fully understood. A large body of evidence places Aβ upstream in the cascade of pathological events, triggering NFTs formation and the subsequent neuron loss. Extracellular Aβ deposits were indeed causative of an increased tau phosphorylation and accumulation in several transgenic models but the contribution of soluble Aβ peptides is still controversial. Among the different Aβ variants, the N-terminally truncated peptide Aβ4–42 is among the most abundant. To understand whether soluble Aβ4–42 peptides impact the onset or extent of tau pathology, we have crossed the homozygous Tg4–42 mouse model of AD, exclusively expressing Aβ4–42 peptides, with the PS19 (P301S) tau transgenic model. Behavioral assessment showed that the resulting double-transgenic line presented a partial worsening of motor performance and spatial memory deficits in the aged group. While an increased loss of distal CA1 pyramidal neurons was detected in young mice, no significant alterations in hippocampal tau phosphorylation were observed in immunohistochemical analyses.
- Published
- 2021
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25. 18F-FDG-PET Detects Drastic Changes in Brain Metabolism in the Tg4–42 Model of Alzheimer’s Disease
- Author
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Caroline Bouter, Philipp Henniges, Timon N. Franke, Caroline Irwin, Carsten Oliver Sahlmann, Marius E. Sichler, Nicola Beindorff, Thomas A. Bayer, and Yvonne Bouter
- Subjects
positron-emission tomography ,18F-Fluorodeoxyglucose ,brain metabolism ,Alzheimer’s disease ,N-truncated Aβ ,neuron loss ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The evaluation of new therapeutic strategies in Alzheimer’s disease (AD) relies heavily on in vivo imaging and suitable animal models that mimic the pathological changes seen in patients. 18F-Fluorodeoxyglucose (18F-FDG)-positron-emission tomography (PET) is a well-established non-invasive imaging tool for monitoring changes in cerebral brain glucose metabolism in vivo. 18F-FDG-PET is used as a functional biomarker for AD as patients show an early and progressive reduction of cerebral glucose metabolism. However, earlier studies in preclinical models of AD showed conflicting results. The aim of this study was the evaluation of cerebral glucose metabolism in the Tg4–42 mouse model of AD using 18F-FDG-PET/magnetic resonance imaging (MRI). Tg4–42 mice show an age-dependent reduction in glucose metabolism together with severe neuron loss and memory deficits. Similar to AD patients early decrease in 18F-FDG uptake was already detected in young (3 months) Tg4–42 mice. The altered glucose metabolism coupled with age- and disease related cognitive decline of Tg4–42 mice make it a well-suited model for preclinical testing of AD-relevant therapeutics.
- Published
- 2019
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26. Establishment of a novel mesial temporal lobe epilepsy rhesus monkey model via intra-hippocampal and intra-amygdala kainic acid injection assisted by neurosurgical robot system.
- Author
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Chen, Yingchuan, Zhu, Guanyu, Shi, Lin, Liu, Defeng, Zhang, Xin, Liu, Yuye, Yuan, Tianshuo, Du, Tingting, and Zhang, Jianguo
- Subjects
- *
TEMPORAL lobe epilepsy , *RHESUS monkeys , *KAINIC acid , *LIMBIC system , *CINGULATE cortex - Abstract
• Stable mTLE-NHP model can be established in an easier way. • SEEG was firstly conducted in mTLE-NHP model to monitor epilepsy zone variation. • Change of Limbic system structures mimic pathology of mTLE patients. Mesial temporal lobe epilepsy (mTLE) is the most common type of refractory epilepsy, and non-human primate (NHP) models are important to investigate its mechanism and therapy. However, previous mTLE-NHP models have some defects. Thirteen rhesus monkeys were randomly assigned to a control group and epilepsy group. Kainic acid (KA) was injected into the left hippocampus and amygdala assisted by a neurosurgical robot system, while the control group received normal saline injection. Stereoelectroencephalography (SEEG) electrodes were implanted into the hippocampus in the acute and chronic stages to monitor epileptic discharges, with continuous behavior monitoring. The changes in hippocampal volume were evaluated by magnetic resonance imaging. Transmission electron microscopy, western blotting and immunofluorescence were performed 3 months after injection to investigate neuronal ultrastructural alteration, blood–brain barrier (BBB) disruption, neuronal loss and gliosis in multiple brain regions. In the epilepsy group, status epilepticus (SE) and spontaneously recurrent seizures (SRSs) were detected in the acute and chronic stages via video monitoring. SEEG confirmed that the epileptic zone was focused on the injection area. The hippocampal volume was significantly decreased in the chronic stage compared with baseline. Neuronal ultrastructure and BBB integrity deteriorated in the hippocampus and amygdala of epileptic monkeys. The obvious neuronal loss and gliosis in the CA1–CA4 hippocampal regions were confirmed by western blotting and immunofluorescence; however, the temporal cortex was not affected. Moreover, the neuronal ultrastructural deterioration was detected in other limbic system regions (orbitofrontal cortex and posterior cingulate cortex). A novel mTLE-NHP model was induced by one-time intra-hippocampal and intra-amygdalar KA injection, with detectable SE and SRS. Severe hippocampal atrophy, neuronal ultrastructural damage, BBB disruption, neuronal loss and gliosis were confirmed in this model, with widespread limbic system damage, which are similar to the pathology of mTLE patients. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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27. N-Terminal Truncated Aβ4-42 Is a Substrate for Neprilysin Degradation in vitro and in vivo.
- Author
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Hornung, Karen, Zampar, Silvia, Engel, Nadine, Klafki, Hans, Liepold, Thomas, Bayer, Thomas A., Wiltfang, Jens, Jahn, Olaf, and Wirths, Oliver
- Subjects
- *
NEPRILYSIN , *ALZHEIMER'S disease , *MASS spectrometry , *TRANSGENIC mice , *PEPTIDES , *AMYLOID , *ANIMAL experimentation , *COMPARATIVE studies , *RESEARCH methodology , *MEDICAL cooperation , *MICE , *NEURONS , *PROTEOLYTIC enzymes , *RESEARCH , *EVALUATION research - Abstract
In sporadic Alzheimer's disease (AD), an imbalance between production and clearance of amyloid-β (Aβ) peptides seems to account for enhanced Aβ accumulation. The metalloprotease neprilysin (NEP) is an important Aβ degrading enzyme as shown by a variety of in vitro and in vivo studies. While the degradation of full-length Aβ peptides such as Aβ1-40 and Aβ1-42 is well established, it is less clear whether NEP is also capable of degrading N-terminally truncated Aβ species such as the common variant Aβ4-42. In the present report, we confirmed the degradation of Aβ4-x species by neprilysin using in vitro digestion and subsequent analysis using gel-based assays and mass spectrometry. By crossing Tg4-42 mice expressing only Aβ4-42 peptides with homozygous NEP-knock-out mice (NEP-/-), we were able to demonstrate that NEP deficiency increased hippocampal intraneuronal Aβ levels and aggravated neuron loss in the Tg4-42 transgenic mouse model of AD. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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28. Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models
- Author
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Oliver Wirths and Silvia Zampar
- Subjects
Alzheimer’s disease ,amyloid β ,neuron loss ,transgenic mice ,Amyloid precursor protein ,intraneuronal Aβ ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Transgenic mouse models represent an essential tool for the exploration of Alzheimer’s disease (AD) pathological mechanisms and the development of novel treatments, which at present provide only symptomatic and transient effects. While a variety of mouse models successfully reflects the main neuropathological hallmarks of AD, such as extracellular amyloid-β (Aβ) deposits, intracellular accumulation of Tau protein, the development of micro- and astrogliosis, as well as behavioral deficits, substantial neuron loss, as a key feature of the disease, seems to be more difficult to achieve. In this review, we summarize information on classic and more recent transgenic mouse models for AD, focusing in particular on loss of pyramidal, inter-, and cholinergic neurons. Although the cause of neuron loss in AD is still a matter of scientific debate, it seems to be linked to intraneuronal Aβ accumulation in several transgenic mouse models, especially in pyramidal neurons.
- Published
- 2020
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29. Synergistic Effect on Neurodegeneration by N-Truncated Aβ4−42 and Pyroglutamate Aβ3−42 in a Mouse Model of Alzheimer's Disease
- Author
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Jose S. Lopez-Noguerola, Nicolai M. E. Giessen, Maximilian Ueberück, Julius N. Meißner, Charlotte E. Pelgrim, Johnathan Adams, Oliver Wirths, Yvonne Bouter, and Thomas A. Bayer
- Subjects
Alzheimer's disease ,N-truncated Aβ ,pyroglutamate Aβ ,neuron loss ,intraneuronal Aβ ,behavior ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The N-terminally truncated pyroglutamate Aβ3−42 (AβpE3−42) and Aβ4−42 peptides are known to be highly abundant in the brain of Alzheimer's disease (AD) patients. Both peptides show enhanced aggregation and neurotoxicity in comparison to full-length Aβ, suggesting that these amyloid peptides may play an important role in the pathogenesis of AD. The aim of the present work was to study the direct effect of the combination of AβpE3−42 and Aβ4−42 on ongoing AD-related neuron loss, pathology, and neurological deficits in transgenic mice. Bigenic mice were generated by crossing the established TBA42 and Tg4-42 mouse models expressing the N-truncated Aβ peptides AβpE3−42 and Aβ4−42, respectively. After generation of the bigenic mice, detailed phenotypical characterization was performed using either immunostainings to evaluate amyloid pathology or quantification of neuron numbers using design-based stereology. The elevated plus maze was used to study anxiety levels. In order to evaluate sensori-motor deficits, the inverted grid, the balance beam and the string suspension tasks were applied. We could demonstrate that co-expression of AβpE3−42 and Aβ4−42 accelerates neuron loss in the CA1 pyramidal layer of young bigenic mice as seen by reduced neuron numbers in comparison to single transgenic homozygous mice expressing either AβpE3−42 or Aβ4−42. This observation coincides with the robust intraneuronal Aβ accumulation observed in the bigenic mice. In addition, loss of anxiety and motor deficits were enhanced in an age-dependent manner. The sensori-motor deficits correlate with the abundant spinal cord pathology, as demonstrated by robust intracellular Aβ accumulation within motor neurons and extracellular Aβ deposition. Our observations demonstrate that a combination of AβpE3−42 and Aβ4−42 has a stronger effect on ongoing AD pathology than the peptides alone. Therefore, AβpE3−42 and Aβ4−42 might represent excellent potential therapeutic targets and diagnostic markers for AD.
- Published
- 2018
- Full Text
- View/download PDF
30. Mechanism of Cellular Formation and In Vivo Seeding Effects of Hexameric β-Amyloid Assemblies
- Author
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Loïc Quinton, Ludovic D'Auria, Vincent Van Pesch, Nuria Suelves, Céline Vrancx, Bernard Hanseeuw, Pascal Kienlen-Campard, Devkee M. Vadukul, Florian Perrin, and Sabrina Contino
- Subjects
Aβ oligomers ,GAMMA-SECRETASE ,A-BETA-40 ,Seeding ,Peptide ,Plaque, Amyloid ,Hexameric A beta ,NEURON LOSS ,Mice ,SYNAPTIC PLASTICITY ,Senile plaques ,chemistry.chemical_classification ,Neurons ,A beta oligomers ,Presenilins ,Brain ,Alzheimer's disease ,ALZHEIMERS-DISEASE ,Neurology ,Cellular model ,Life Sciences & Biomedicine ,Alzheimer’s disease ,Genetically modified mouse ,PRESENILIN-1 ,FAD model ,Neuroscience (miscellaneous) ,Context (language use) ,Mice, Transgenic ,CHO Cells ,PROTEIN A-BETA ,Presenilin ,Article ,Cellular and Molecular Neuroscience ,Cricetulus ,In vivo ,Alzheimer Disease ,Cell Line, Tumor ,Animals ,Humans ,Hexameric Aβ ,Science & Technology ,Amyloid beta-Peptides ,Neurosciences ,AGGREGATION ,Fibroblasts ,TRANSMEMBRANE DOMAIN ,In vitro ,PATHOLOGY ,chemistry ,Biophysics ,Neurosciences & Neurology - Abstract
The β-amyloid peptide (Aβ) is the main constituent of senile plaques, a typical hallmark of Alzheimer’s disease (AD). Monomeric Aβ is generated through sequential processing of the amyloid precursor protein (APP), with a final step involving γ-secretase activity. In AD, Aβ monomers assemble in oligomers and ultimately fibrils depositing in plaques. Importantly, Aβ toxicity appears related to its soluble oligomeric intermediates. In particular, recombinant Aβ studies described Aβ hexamers as critical oligomeric nuclei. We recently identified hexameric Aβ assemblies in a cellular model, and revealed their ability to enhance recombinant Aβ aggregation in vitro. Here, we assessed the contribution of similar hexameric-like Aβ assemblies to the development of amyloid pathology. We report their early presence in both transgenic mice brains exhibiting human Aβ pathology and cerebrospinal fluid of AD patients, suggesting hexameric Aβ as a putative novel AD biomarker. Using isolated cell-derived hexameric Aβ, we report the potential of these assemblies to seed other human Aβ species, resulting in neuronal toxicity in vitro and amyloid deposition aggravation in vivo. In order to identify key contributors to their formation in a cellular context, we investigated the role of presenilin-1 (PS1) and presenilin-2 (PS2) in the formation of hexameric-like Aβ assemblies. As catalytic subunits of the γ-secretase complex, PS1 and PS2 can differentially participate in Aβ generation. Using CRISPR-Cas9-modified neuronal-like cell lines knockdown for each of the two presenilins, we present experimental evidence suggesting a direct link between the PS2-dependent pathway and the release of hexameric-like Aβ assemblies in extracellular vesicles.
- Published
- 2021
31. Hippocampal sclerosis, hippocampal neuron loss patterns and TDP‐43 in the aged population.
- Author
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Hokkanen, Suvi R. K., Hunter, Sally, Polvikoski, Tuomo M., Keage, Hannah A. D., Minett, Thais, Matthews, Fiona E., Brayne, Carol, and MRC CFAS and CC75C Study Group
- Subjects
- *
HIPPOCAMPUS diseases , *MULTIPLE sclerosis , *NEURODEGENERATION , *TDP-43 proteinopathies , *ETIOLOGY of diseases - Abstract
Abstract: Hippocampal neuron loss is a common neuropathological feature in old age with various underlying etiologies. Hippocampal sclerosis of aging (HS‐Aging) is neuropathologically characterized by severe CA1 neuronal loss and frequent presence of transactive response DNA‐binding protein of 43 kDa (TDP‐43) aggregations. Its etiology is unclear and currently no standardized approaches to measure HS‐Aging exist. We developed a semi‐quantitative protocol, which captures various hippocampal neuron loss patterns, and compared their occurrence in the context of HS‐Aging, TDP‐43, vascular and tau pathology in 672 brains (TDP‐43 staining n = 642/672, 96%) donated for the population‐based Cambridge City over‐75s Cohort and the Cognitive Function and Ageing Study. HS‐Aging was first evaluated independently from the protocol using the most common criteria defined in literature, and then described in detail through examination of neuron loss patterns and associated pathologies. 34 (5%) cases were identified, with a maximum of five pyramidal neurons in each of over half CA1 fields‐of‐view (x200 magnification), no vascular damage, no neuron loss in CA2‐CA4, but consistent TDP‐43 neuronal solid inclusions and neurites. We also report focal CA1 neuron loss with vascular pathology to affect predominantly CA1 bordering CA2 (Fisher's exact, P = 0.009), whereas neuron loss in the subicular end of CA1 was associated with TDP‐43 inclusions (Fisher's exact, P < 0.001) and high Braak stage (Fisher's exact, P = 0.001). Hippocampal neuron loss in CA4‐CA2 was not associated with TDP‐43. We conclude that hippocampal neuron loss patterns are associated with different etiologies within CA1, and propose that these patterns can be used to form objective criteria for HS‐Aging diagnosis. Finally, based on our results we hypothesize that neuron loss leading to HS‐Aging starts from the subicular end of CA1 when it is associated with TDP‐43 pathology, and that this neurodegenerative process is likely to be significantly more common than “end‐stage” HS‐Aging only. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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32. Synergistic Effect on Neurodegeneration by N-Truncated Aβ4-42 and Pyroglutamate Aβ3-42 in a Mouse Model of Alzheimer's Disease.
- Author
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Lopez-Noguerola, Jose S., Giessen, Nicolai M. E., Ueberück, Maximilian, Meißner, Julius N., Pelgrim, Charlotte E., Adams, Johnathan, Wirths, Oliver, Bouter, Yvonne, and Bayer, Thomas A.
- Subjects
NEURODEGENERATION ,ALZHEIMER'S patients ,GLUTAMIC acid ,NEUROTOXICOLOGY ,IMMUNOSTAINING - Abstract
The N-terminally truncated pyroglutamate Aβ
3-42 (AαpE3-42 ) and Aα2-42 peptides are known to be highly Aαundant in the brain of Alzheimer's disease (AD) patients. Both peptides show enhanced aggregation and neurotoxicity in comparison to full-length Aα, suggesting that these amyloid peptides may play an important role in the pathogenesis of AD. The aim of the present work was to study the direct effect of the combination of AαpE3-42 and Aα2-42 on ongoing AD-related neuron loss, pathology, and neurological deficits in transgenic mice. Bigenic mice were generated by crossing the established TBA42 and Tg4-42 mouse models expressing the N-truncated Aα peptides AαpE3-42 and Aα2-42 , respectively. After generation of the bigenic mice, detailed phenotypical characterization was performed using either immunostainings to evaluate amyloid pathology or quantification of neuron numbers using design-based stereology. The elevated plus maze was used to study anxiety levels. In order to evaluate sensori-motor deficits, the inverted grid, the balance beam and the string suspension tasks were applied. We could demonstrate that co-expression of AαpE3-42 and Aα2-42 accelerates neuron loss in the CA1 pyramidal layer of young bigenic mice as seen by reduced neuron numbers in comparison to single transgenic homozygous mice expressing either AαpE3-42 or Aα2-42 . This observation coincides with the robust intraneuronal Aα accumulation observed in the bigenic mice. In addition, loss of anxiety and motor deficits were enhanced in an age-dependent manner. The sensori-motor deficits correlate with the abundant spinal cord pathology, as demonstrated by robust intracellular Aα accumulation within motor neurons and extracellular Aα deposition. Our observations demonstrate that a combination of AαpE3-42 and Aα2-42 has a stronger effect on ongoing AD pathology than the peptides alone. Therefore, AαpE3-42 and Aα2-42 might represent excellent potential therapeutic targets and diagnostic markers for AD. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
33. Conditional Deletion of PDK1 in the Forebrain Causes Neuron Loss and Increased Apoptosis during Cortical Development
- Author
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Congyu Xu, Linjie Yu, Jinxing Hou, Rosemary J. Jackson, He Wang, Chaoli Huang, Tingting Liu, Qihui Wang, Xiaochuan Zou, Richard G. Morris, Tara L. Spires-Jones, Zhongzhou Yang, Zhenyu Yin, Yun Xu, and Guiquan Chen
- Subjects
PDK1 ,Akt ,mTOR ,neuron loss ,apoptosis ,learning and memory ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Decreased expression but increased activity of PDK1 has been observed in neurodegenerative disease. To study in vivo function of PDK1 in neuron survival during cortical development, we generate forebrain-specific PDK1 conditional knockout (cKO) mice. We demonstrate that PDK1 cKO mice display striking neuron loss and increased apoptosis. We report that PDK1 cKO mice exhibit deficits on several behavioral tasks. Moreover, PDK1 cKO mice show decreased activities for Akt and mTOR. These results highlight an essential role of endogenous PDK1 in the maintenance of neuronal survival during cortical development.
- Published
- 2017
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34. Iron Exposure and the Cellular Mechanisms Linked to Neuron Degeneration in Adult Mice
- Author
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Lin-Bo Li, Rui Chai, Shuai Zhang, Shuang-Feng Xu, Yan-Hui Zhang, Hai-Long Li, Yong-Gang Fan, and Chuang Guo
- Subjects
Alzheimer’s disease ,iron ,neuron loss ,apoptosis ,autophagy ,ferroptosis ,Cytology ,QH573-671 - Abstract
Although the causal relationship between Alzheimer’s disease (AD) and iron overload remains unclear, iron dyshomeostasis or improper transport mechanisms are speculated to lead to the accumulation of this neurotoxic metal in the hippocampal formation and other cerebral areas related to neurodegenerative diseases, resulting in the formation of reactive oxygen species (ROS) and, ultimately, cell death. In this study, exposure to high dietary iron (HDI) revealed no significant difference in the number of iron-positive cells and iron content in the cortex and hippocampal region between wild-type (WT) and APP/PS1 mice; however, compared with the control mice, the HDI-treated mice exhibited upregulated divalent metal transporter 1 (DMT1) and ferroportin (Fpn) expression, and downregulated transferrin receptor (TFR) expression. Importantly, we confirmed that there were significantly fewer NeuN-positive neurons in both APP/PS1 and WT mice given HDI, than in the respective controls. Moreover, this iron-induced neuron loss may involve increased ROS and oxidative mitochondria dysfunction, decreased DNA repair, and exacerbated apoptosis and autophagy. Although HDI administration might trigger protective antioxidant, anti-apoptosis, and autophagy signaling, especially in pathological conditions, these data clearly indicate that chronic iron exposure results in neuronal loss due to apoptosis, autophagy, and ferroptosis, hence increasing the risk for developing AD.
- Published
- 2019
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35. Prenatal Lipopolysaccharide Alters Postnatal Dopamine in the Laboratory Rat
- Author
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Ling, Zaodung, Gayle, Dave A., Lipton, Jack W., Carvey, Paul M., Nagatsu, Toshiharu, editor, Nabeshima, Toshitaka, editor, McCarty, Richard, editor, and Goldstein, David S., editor
- Published
- 2002
- Full Text
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36. Cerebrospinal fluid proteomics reveal potential protein targets of JiaWeiSiNiSan in preventing chronic psychological stress damage
- Author
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Ling Li, Han-Zhang Wang, Wu-Long Luo, Ning-Xi Zeng, Can Yan, Lili Wu, and Hui-Zhen Li
- Subjects
Male ,Proteomics ,Quantitative proteomics ,Pharmaceutical Science ,Hippocampus ,Context (language use) ,RM1-950 ,Pharmacology ,Immunofluorescence ,Cerebrospinal fluid ,Drug Discovery ,medicine ,Animals ,Rats, Wistar ,Behavior, Animal ,medicine.diagnostic_test ,Depression ,business.industry ,Dentate gyrus ,Stress resilience ,General Medicine ,UBA1 ,Resilience, Psychological ,hippocampus neurogenesis ,Rats ,Disease Models, Animal ,Complementary and alternative medicine ,neuron loss ,Chronic Unpredictable Mild Stress model ,Molecular Medicine ,Therapeutics. Pharmacology ,business ,Stress, Psychological ,Drugs, Chinese Herbal ,Research Article - Abstract
Context Chinese herbal formula JiaWeiSiNiSan (JWSNS) has been widely used to prevent stress-induced neuropsychiatric ailments in clinics and proven to have therapeutic anti-stress effects on rats. However, the mechanism remains unclear. Objective Based on the proteomics of cerebrospinal fluid (CSF), this study explores the possible mechanism and target proteins of JiaWeiSiNiSan raising stress resilience and preventing stress damage. Materials and methods A 6-week Chronic Unpredictable Mild Stress (CUMS) model was applied on adult Wistar male rats to observe the effects of JWSNS on improving mental stress resilience. Tandem Mass Tag (TMT) proteomics and bioinformatics analysis were used to screen and analyze differentially expressed proteins (DEPs) in CSF. Parallel Reaction Monitoring (PRM) was used to validate target DEPs. Results Significantly decreased sucrose preference, locomotion activity level and accuracy of T-maze, as well as increased immobility time, were observed in CUMS rats compared to CON rats while JWSNS improved above depression-like behaviours. The quantitative proteomics and bioinformatics analysis showed that JWSNS decreased the expression of Rps4x, HSP90AA1, Rps12, Uba1, Rsp14, Tuba1b in CUMS rats CSF (p
- Published
- 2021
37. Combined treatment with valproic acid and estrogen has neuroprotective effects in ovariectomized mice with Alzheimer’s disease
- Author
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Yuanjie Liu, Wei Zhang, Yan-Zhen Li, Xin Zhou, Shifang Luo, and Guiqiong He
- Subjects
0301 basic medicine ,medicine.medical_specialty ,17β-estradiol ,amyloid β ,dementia ,estrogen receptor α ,estrogen receptor β ,glycogen synthase kinase-3β ,liquiritigenin ,menopause ,neuron loss ,tau ,medicine.drug_class ,medicine.medical_treatment ,Intraperitoneal injection ,Estrogen receptor ,lcsh:RC346-429 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Developmental Neuroscience ,GSK-3 ,Internal medicine ,medicine ,lcsh:Neurology. Diseases of the nervous system ,Valproic Acid ,business.industry ,medicine.disease ,Menopause ,030104 developmental biology ,Endocrinology ,chemistry ,Estrogen ,Ovariectomized rat ,lipids (amino acids, peptides, and proteins) ,Liquiritigenin ,business ,030217 neurology & neurosurgery ,medicine.drug ,Research Article - Abstract
Postmenopausal women with Alzheimer's disease (AD) exhibit dramatically reduced sensitivity to estrogen replacement therapy, which is though to be related to an estrogen receptor (ER)α/ERβ ratio imbalance arising from a significantly decreased level of ERs of the brain. The aim of our study was to investigate whether valproic acid (VPA) can enhance the beneficial effects of estrogen on cognitive function through restoration of ERα and ERβ expression in the brain. We removed the ovaries of female APP/PS1 mice to simulate the low estrogen levels present in postmenopausal women and then administered VPA (30 mg/kg, intraperitoneal injection, once daily), 17β-estradiol (E2) (2.4 μg, intraperitoneal injection, once daily), liquiritigenin (LG) (50 μg/kg, intragastric infusion, once daily), VPA + E2, or VPA + LG for 4 successive weeks. Compared with treatment with a single drug, treatment with VPA + E2 or VPA + LG significantly increased the level of glycogen synthase kinase 3β, increased the expression of estrogen receptor α, reduced the expression of small ubiquitin-like modifiers, and increased the level of estrogen receptor β. This resulted in enhanced sensitivity to estrogen therapy, reduced amyloid β aggregation, reduced abnormal phosphorylation of the tau protein, reduced neuronal loss, increased dendritic spine and postsynaptic density, and significantly alleviated memory loss and learning impairment in mice. This study was approved by the Chongqing Medical University Animal Protection and Ethics Committee, China on March 6, 2013.
- Published
- 2021
38. LW-AFC, a new formula derived from Liuwei Dihuang decoction, ameliorates behavioral and pathological deterioration via modulating the neuroendocrine-immune system in PrP-hAβPPswe/PS1ΔE9 transgenic mice.
- Author
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Jian-Hui Wang, Xi Lei, Xiao-Rui Cheng, Xiao-Rui Zhang, Gang Liu, Jun-Ping Cheng, Yi-Ran Xu, Ju Zeng, Wen-Xia Zhou, and Yong-Xiang Zhang
- Subjects
- *
ALZHEIMER'S disease , *POLYSACCHARIDES , *GLYCOSIDE synthesis , *OLIGOSACCHARIDES , *NEUROENDOCRINE system , *AMYLOID beta-protein - Abstract
Background: Accumulating evidence implicates the neuroendocrine immunomodulation (NIM) network in the physiopathological mechanism of Alzheimer's disease (AD). Notably, we previously revealed that the NIM network is dysregulated in the PrP-hAβPPswe/PS1ΔE9 (APP/PS1) transgenic mouse model of AD. Methods: After treatment with a novel Liuwei Dihuang formula (LW-AFC), mice were cognitively evaluated in behavioral experiments. Neuron loss, amyloid-β (Aβ) deposition, and Aβ level were analyzed using Nissl staining, immunofluorescence, and an AlphaLISA assay, respectively. Multiplex bead analysis, a radioimmunoassay, immunochemiluminometry, and an enzyme-linked immunosorbent assay (ELISA) were used to measure cytokine and hormone levels. Lymphocyte subsets were detected using flow cytometry. Data between two groups were compared using a Student's t test. Comparison of the data from multiple groups against one group was performed using a one-way analysis of variance (ANOVA) followed by a Dunnett's post hoc test or a two-way repeated-measures analysis of variance with a Tukey multiple comparisons test. Results: LW-AFC ameliorated the cognitive impairment observed in APP/PS1 mice, including the impairment of object recognition memory, spatial learning and memory, and active and passive avoidance. In addition, LW-AFC alleviated the neuron loss in the hippocampus, suppressed Aβ deposition in the brain, and reduced the concentration of Aβ1-42 in the hippocampus and plasma of APP/PS1 mice. LW-AFC treatment also significantly decreased the secretion of corticotropin-releasing hormone and gonadotropin-releasing hormone in the hypothalamus, and adrenocorticotropic hormone, luteinizing hormone, and follicle-stimulating hormone in the pituitary. Moreover, LW-AFC increased CD8+CD28+ T cells, and reduced CD4+CD25+Foxp3+ T cells in the spleen lymphocytes, downregulated interleukin (IL)-1β, IL-2, IL-6, IL-23, granulocyte-macrophage colony stimulating factor, and tumor necrosis factor-α and -β, and upregulated IL-4 and granulocyte colony stimulating factor in the plasma of APP/PS1 mice. Conclusions: LW-AFC ameliorated the behavioral and pathological deterioration of APP/PS1 transgenic mice via the restoration of the NIM network to a greater extent than either memantine or donepezil, which supports the use of LW-AFC as a potential agent for AD therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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39. Mild traumatic brain injury produces neuron loss that can be rescued by modulating microglial activation using a CB2 receptor inverse agonist
- Author
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Anton Reiner, Wei Bu, Huiling Ren, Yunping Deng, Nobel Del Mar, Natalie Hart Guley, Bob M Moore, and Marcia G Honig
- Subjects
Cerebral Cortex ,Striatum ,basolateral amygdala ,neuron loss ,Traumatic brain injury (TBI) ,neuron rescue ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
We have previously reported that mild TBI created by focal left-side cranial blast in mice produces widespread axonal injury, microglial activation, and a variety of functional deficits. We have also shown that these functional deficits are reduced by targeting microglia through their cannabinoid type-2 (CB2) receptors using two-week daily administration of the CB2 inverse agonist SMM-189. CB2 inverse agonists stabilize the G-protein coupled CB2 receptor in an inactive conformation, leading to increased phosphorylation and nuclear translocation of the cAMP response element binding protein (CREB), and thus bias activated microglia from a pro-inflammatory M1 to a pro-healing M2 state. In the present study, we showed that SMM-189 boosts nuclear pCREB levels in microglia in several brain regions by 3 days after TBI, by using pCREB/CD68 double immunofluorescent labeling. Next, to better understand the basis of motor deficits and increased fearfulness after TBI, we used unbiased stereological methods to characterize neuronal loss in cortex, striatum, and basolateral amygdala (BLA) and assessed how neuronal loss was affected by SMM-189 treatment. Our stereological neuron counts revealed a 20% reduction in cortical and 30% reduction in striatal neurons bilaterally at 2-3 months post blast, with SMM-189 yielding about 50% rescue. Loss of BLA neurons was restricted to the blast side, with 33% of Thy1+ fear-suppressing pyramidal neurons and 47% of fear-suppressing parvalbuminergic (PARV) interneurons lost, and Thy1-negative fear-promoting pyramidal neurons not significantly affected. SMM-189 yielded 50-60% rescue of Thy1+ and PARV neuron loss in BLA. Thus, fearfulness after mild TBI may result from the loss of fear-suppressing neuron types in BLA, and SMM-189 may reduce fearfulness by their rescue. Overall, our findings indicate that SMM-189 rescues damaged neurons and thereby alleviates functional deficits resulting from TBI, apparently by selectively modulating microglia to the beneficial M2 state. CB2 inverse agonists thus represent a promising therapeutic approach for mitigating neuroinflammation and neurodegeneration.
- Published
- 2016
- Full Text
- View/download PDF
40. Chronic Memantine Treatment Ameliorates Behavioral Deficits, Neuron Loss, and Impaired Neurogenesis in a Model of Alzheimer’s Disease
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Oliver Wirths and Martina Stazi
- Subjects
0301 basic medicine ,Genetically modified mouse ,Amyloid ,Neurogenesis ,Neuroscience (miscellaneous) ,Administration, Oral ,Morris water navigation task ,Mice, Transgenic ,Anxiety ,Motor Activity ,Hippocampal formation ,Neuroprotection ,Article ,Neuron loss ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Alzheimer Disease ,Memantine ,medicine ,Animals ,Transgenic mice ,CA1 Region, Hippocampal ,Spatial Memory ,Neurons ,Behavior ,Behavior, Animal ,business.industry ,Neurodegeneration ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,Neurology ,Alzheimer ,NMDA receptor ,business ,Open Field Test ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Memantine, a non-competitive NMDA receptor antagonist possessing neuroprotective properties, belongs to the small group of drugs which have been approved for the treatment of Alzheimer’s disease (AD). While several preclinical studies employing different transgenic AD mouse models have described beneficial effects with regard to rescued behavioral deficits or reduced amyloid plaque pathology, it is largely unknown whether memantine might have beneficial effects on neurodegeneration. In the current study, we assessed whether memantine treatment has an impact on hippocampal neuron loss and associated behavioral deficits in the Tg4-42 mouse model of AD. We demonstrate that a chronic oral memantine treatment for 4 months diminishes hippocampal CA1 neuron loss and rescues learning and memory performance in different behavioral paradigms, such as Morris water maze or a novel object recognition task. Cognitive benefits of chronic memantine treatment were accompanied by an amelioration of impaired adult hippocampal neurogenesis. Taken together, our results demonstrate that memantine successfully counteracts pathological alterations in a preclinical mouse model of AD. Electronic supplementary material The online version of this article (10.1007/s12035-020-02120-z) contains supplementary material, which is available to authorized users.
- Published
- 2020
41. A novel and accurate full-length HTT mouse model for Huntington’s disease
- Author
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Sushuang Zheng, Sushila A Shenoy, Wencheng Liu, Yuanyi Dai, Yuanxiu Liu, Zhipeng Hou, Susumu Mori, Yi Tang, Jerry Cheng, Wenzhen Duan, and Chenjian Li
- Subjects
Male ,Chromosomes, Artificial, Bacterial ,huntington's disease ,QH301-705.5 ,Science ,Mice, Transgenic ,Body weight loss ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Animals ,Humans ,Biology (General) ,Htt aggregates ,Huntingtin Protein ,General Immunology and Microbiology ,General Neuroscience ,neurodegeneration ,General Medicine ,Human BAC ,transgenic mouse ,Disease Models, Animal ,Huntington Disease ,neuron loss ,Medicine ,Female ,brain atrophy ,Research Article ,Neuroscience ,Huntington’s disease - Abstract
Here, we report the generation and characterization of a novel Huntington’s disease (HD) mouse model BAC226Q by using a bacterial artificial chromosome (BAC) system, expressing full-length human HTT with ~226 CAG-CAA repeats and containing endogenous human HTT promoter and regulatory elements. BAC226Q recapitulated a full-spectrum of age-dependent and progressive HD-like phenotypes without unwanted and erroneous phenotypes. BAC226Q mice developed normally, and gradually exhibited HD-like psychiatric and cognitive phenotypes at 2 months. From 3 to 4 months, BAC226Q mice showed robust progressive motor deficits. At 11 months, BAC226Q mice showed significant reduced life span, gradual weight loss and exhibited neuropathology including significant brain atrophy specific to striatum and cortex, striatal neuronal death, widespread huntingtin inclusions, and reactive pathology. Therefore, the novel BAC226Q mouse accurately recapitulating robust, age-dependent, progressive HD-like phenotypes will be a valuable tool for studying disease mechanisms, identifying biomarkers, and testing gene-targeting therapeutic approaches for HD.
- Published
- 2022
42. The association between neurodegeneration and local complement activation in the thalamus to progressive multiple sclerosis outcome
- Author
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Benjamin J. Cooze, Matthew Dickerson, Rukshikah Loganathan, Lewis M. Watkins, Ethan Grounds, Ben R. Pearson, Ryan Jack Bevan, B. Paul Morgan, Roberta Magliozzi, Richard Reynolds, James W. Neal, and Owain W. Howell
- Subjects
Multiple Sclerosis ,General Neuroscience ,CSF ,Multiple Sclerosis, Chronic Progressive ,Pathology and Forensic Medicine ,Thalamus ,neuron loss ,Humans ,Neurology (clinical) ,meningeal inflammation ,microglial activation ,Atrophy ,Gray Matter ,Complement Activation - Abstract
The extent of grey matter demyelination and neurodegeneration in the progressive multiple sclerosis (PMS) brains at post-mortem associates with more severe disease. Regional tissue atrophy, especially affecting the cortical and deep grey matter, including the thalamus, is prognostic for poor outcomes. Microglial and complement activation are important in the pathogenesis and contribute to damaging processes that underlie tissue atrophy in PMS. We investigated the extent of pathology and innate immune activation in the thalamus in comparison to cortical grey and white matter in blocks from 21 cases of PMS and 10 matched controls. Using a digital pathology workflow, we show that the thalamus is invariably affected by demyelination and had a far higher proportion of active inflammatory lesions than forebrain cortical tissue blocks from the same cases. Lesions were larger and more frequent in the medial nuclei near the ventricular margin, whilst neuronal loss was greatest in the lateral thalamic nuclei. The extent of thalamic neuron loss was not associated with thalamic demyelination but correlated with the burden of white matter pathology in other forebrain areas (Spearman r = 0.79, p 0.0001). Only thalamic neuronal loss, and not that seen in other forebrain cortical areas, correlated with disease duration (Spearman r = -0.58, p = 0.009) and age of death (Spearman r = -0.47, p = 0.045). Immunoreactivity for the complement pattern recognition molecule C1q, and products of complement activation (C4d, Bb and C3b) were elevated in thalamic lesions with an active inflammatory pathology. Complement regulatory protein, C1 inhibitor, was unchanged in expression. We conclude that active inflammatory demyelination, neuronal loss and local complement synthesis and activation in the thalamus, are important to the pathological and clinical disease outcomes of PMS.
- Published
- 2021
43. CERTL reduces C16 ceramide, amyloid-β levels, and inflammation in a model of Alzheimer’s disease
- Author
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Daan van Kruining, Anna-Lena Scheithauer, Pilar Martinez-Martinez, Barbara Hobo, Jochen Walter, Dušan Berkeš, Christopher Exley, Kristiaan Wouters, Mario Losen, Joost Verhaagen, Sandra den Hoedt, Caterina Giovagnoni, Maria Dolores Ledesma, Qian Luo, Matthew Mold, Michelle M. Mielke, Gerard H. Bode, Daniel L.A. van den Hove, Simone M. Crivelli, Jo Stevens, Helga E. de Vries, Erhard Bieberich, Monique T. Mulder, RS: MHeNs - R3 - Neuroscience, Psychiatrie & Neuropsychologie, Interne Geneeskunde, RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome, Netherlands Institute for Neuroscience (NIN), Internal Medicine, Molecular and Cellular Neurobiology, Amsterdam Neuroscience - Neurodegeneration, Molecular cell biology and Immunology, ACS - Microcirculation, Amsterdam Neuroscience - Neuroinfection & -inflammation, and Amsterdam Neuroscience - Neurovascular Disorders
- Subjects
0301 basic medicine ,Sphingomyelin ,alzheimer's disease (ad) ,Adeno-associated virus (AAV) ,Alzheimer’s disease (AD) ,lcsh:RC346-429 ,Ceramide ,chemistry.chemical_compound ,NEURON LOSS ,0302 clinical medicine ,Neuroinflammation ,Amyloid precursor protein ,PEPTIDE ,BRAIN ,IN-VIVO ,TRANSGENIC MICE ,biology ,Microglia ,SPHINGOLIPID METABOLISM ,Amyloid-β plaques ,RC346 ,5xFAD ,Cell biology ,medicine.anatomical_structure ,Neurology ,Ceramide transporter protein (CERT) ,Cognitive Neuroscience ,PRECURSOR APP ,lcsh:RC321-571 ,ANTIGEN-BINDING PROTEIN ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,medicine ,TRAFFICKING ,amyloid-beta plaques ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,lcsh:Neurology. Diseases of the nervous system ,5XFAD MOUSE MODEL ,HEK 293 cells ,Neurotoxicity ,RC521 ,medicine.disease ,Sphingolipid ,030104 developmental biology ,chemistry ,biology.protein ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
BackgroundDysregulation of ceramide and sphingomyelin levels have been suggested to contribute to the pathogenesis of Alzheimer’s disease (AD). Ceramide transfer proteins (CERTs) are ceramide carriers which are crucial for ceramide and sphingomyelin balance in cells. Extracellular forms of CERTs co-localize with amyloid-β (Aβ) plaques in AD brains. To date, the significance of these observations for the pathophysiology of AD remains uncertain.MethodsA plasmid expressing CERTL, the long isoform of CERTs, was used to study the interaction of CERTLwith amyloid precursor protein (APP) by co-immunoprecipitation and immunofluorescence in HEK cells. The recombinant CERTLprotein was employed to study interaction of CERTLwith amyloid-β (Aβ), Aβ aggregation process in presence of CERTL, and the resulting changes in Aβ toxicity in neuroblastoma cells. CERTLwas overexpressed in neurons by adeno-associated virus (AAV) in a mouse model of familial AD (5xFAD). Ten weeks after transduction, animals were challenged with behavior tests for memory, anxiety, and locomotion. At week 12, brains were investigated for sphingolipid levels by mass spectrometry, plaques, and neuroinflammation by immunohistochemistry, gene expression, and/or immunoassay.ResultsHere, we report that CERTLbinds to APP, modifies Aβ aggregation, and reduces Aβ neurotoxicity in vitro. Furthermore, we show that intracortical injection of AAV, mediating the expression of CERTL, decreases levels of ceramide d18:1/16:0 and increases sphingomyelin levels in the brain of male 5xFAD mice. CERTLin vivo over-expression has a mild effect on animal locomotion, decreases Aβ formation, and modulates microglia by decreasing their pro-inflammatory phenotype.ConclusionOur results demonstrate a crucial role of CERTLin regulating ceramide levels in the brain, in amyloid plaque formation and neuroinflammation, thereby opening research avenues for therapeutic targets of AD and other neurodegenerative diseases.
- Published
- 2021
44. Long-term Effects of Multiple Glucocorticoid Exposures in Neonatal Mice
- Author
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Susan E. Maloney, Kevin K. Noguchi, David F. Wozniak, Stephen C. Fowler, and Nuri B. Farber
- Subjects
glucocorticoid ,dexamethasone ,neuromotor deficits ,motor co-ordination ,complex activity wheel ,cerebellum ,internal granule layer ,neuron loss ,apoptotic cell death ,Psychology ,BF1-990 - Abstract
Glucocorticoids (GCs) such as dexamethasone (DEX) or betamethasone are repeatedly administered for up to a month to prematurely born infants as a treatment for chronic lung dysfunction. Results of clinical trials have shown that the use of GCs in these infants induces long-term deficits in neuromotor function and cognition. We have previously shown that a single exposure to clinically relevant doses of DEX or other GCs in the mouse during a period corresponding to the human perinatal period produces a dramatic increase in apoptotic cell death of neural progenitor cells in the developing cerebellum. To provide a model approximating more chronic clinical dosing regimens, we evaluated possible behavioral effects resulting from repeated exposures to DEX and subsequent GC-induced neuronal loss where neonatal mouse pups were injected with 3.0 mg/kg DEX or saline on postnatal days 7, 9, and 11 (DEX3 treatment). Adult, DEX3-treated mice exhibited long-term, possibly permanent, neuromotor deficits on a complex activity wheel task, which requires higher-order motor co-ordination skills. DEX3 mice exhibited impaired performance on this task relative to saline controls in each of two independent studies involving separate cohorts of mice. Histopathology studies utilizing stereological neuronal counts conducted in behaviorally-tested mice showed that the DEX3 treatment resulted in a significant decrease in the number of neurons in the internal granule layer (IGL) of the cerebellum, although the number of neurons in the Purkinje cell layer were unchanged. The results suggest that multiple neonatal DEX exposures can produce chronic deficits in fine motor co-ordination that are associated with cerebellar IGL neuronal loss.
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- 2011
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45. A comparison of mtDNA deletion mutant proliferation mechanisms.
- Author
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Holt, Alan G. and Davies, Adrian M.
- Subjects
- *
DELETION mutation , *MITOCHONDRIAL DNA , *CELL determination - Abstract
In this paper we use simulation methods to investigate the proliferation of deletion mutations of mitochondrial DNA in neurons. We simulate three mtDNA proliferation mechanisms, namely, random drift, replicative advantage and vicious cycle. For each mechanism, we investigated the effect mutation rates have on neuron loss within a human host. We also compare heteroplasmy of each mechanism at mutation rates that yield the levels neuron loss that would be associated with dementia. Both random drift and vicious cycle predicted high levels of heteroplasmy, while replicative advantage showed a small number of dominant clones with a low background of heteroplasmy. • Creation of a simulated environment where mtDNA expire, replicate, mutate and compete. Within this environment, mtDNA deletions behave selfishly thus forming a Darwinian microcosm. • Determination of cell loss rates for three mtDNA deletion proliferation mechanisms, namely, random drift, replicative advantage , and vicious cycle. of mutation rates. • Comparison of each mechanism with regard to heteroplasmy in order to assess which mechanism best predicts mtDNA deletion proliferation. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
46. Mild Traumatic Brain Injury Produces Neuron Loss That Can Be Rescued by Modulating Microglial Activation Using a CB2 Receptor Inverse Agonist.
- Author
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Wei Bu, Huiling Ren, Yunping Deng, Del Mar, Nobel, Guley, Natalie M., Moore, Bob M., G. Honig, Marcia G., and Reiner, Anton
- Subjects
BRAIN injuries ,MICROGLIA ,CANNABINOID receptors - Abstract
We have previously reported that mild TBI created by focal left-side cranial blast in mice produces widespread axonal injury, microglial activation, and a variety of functional deficits. We have also shown that these functional deficits are reduced by targeting microglia through their cannabinoid type-2 (CB2) receptors using 2-week daily administration of the CB2 inverse agonist SMM-189. CB2 inverse agonists stabilize the G-protein coupled CB2 receptor in an inactive conformation, leading to increased phosphorylation and nuclear translocation of the cAMP response element binding protein (CREB), and thus bias activated microglia from a pro-inflammatory M1 to a pro-healing M2 state. In the present study, we showed that SMM-189 boosts nuclear pCREB levels in microglia in several brain regions by 3 days after TBI, by using pCREB/CD68 double immunofluorescent labeling. Next, to better understand the basis of motor deficits and increased fearfulness after TBI, we used unbiased stereological methods to characterize neuronal loss in cortex, striatum, and basolateral amygdala (BLA) and assessed how neuronal loss was affected by SMM-189 treatment. Our stereological neuron counts revealed a 20% reduction in cortical and 30% reduction in striatal neurons bilaterally at 2-3 months post blast, with SMM-189 yielding about 50% rescue. Loss of BLA neurons was restricted to the blast side, with 33% of Thy1+ fear-suppressing pyramidal neurons and 47% of fear-suppressing parvalbuminergic (PARV) interneurons lost, and Thy1-negative fear-promoting pyramidal neurons not significantly affected. SMM-189 yielded 50-60% rescue of Thy1+ and PARV neuron loss in BLA. Thus, fearfulness after mild TBI may result from the loss of fear-suppressing neuron types in BLA, and SMM-189 may reduce fearfulness by their rescue. Overall, our findings indicate that SMM-189 rescues damaged neurons and thereby alleviates functional deficits resulting from TBI, apparently by selectively modulating microglia to the beneficial M2 state. CB2 inverse agonists thus represent a promising therapeutic approach for mitigating neuroinflammation and neurodegeneration. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
47. Dync1h1 Mutation Causes Proprioceptive Sensory Neuron Loss and Impaired Retrograde Axonal Transport of Dorsal Root Ganglion Neurons.
- Author
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Zhao, Jing, Wang, Yi, Xu, Huan, Fu, Yuan, Qian, Ting, Bo, Deng, Lu, Yan ‐ Xin, Xiong, Yi, Wan, Jun, Zhang, Xiang, Dong, Qiang, and Chen, Xiang ‐ Jun
- Subjects
- *
GENETIC mutation , *PROPRIOCEPTION , *SENSORY neurons , *RETROGRADE amnesia , *DORSAL root ganglia - Abstract
Background and Purpose Sprawling ( Swl) is a radiation-induced mutation which has been identified to have a nine base pair deletion in dynein heavy chain 1 (DYNC1H1: encoded by a single gene Dync1h1). This study is to investigate the phenotype and the underlying mechanism of the Dync1h1 mutant. Methods and Results To display the phenotype of Swl mutant mice, we examined the embryos of homozygous ( Swl/Swl) and heterozygous ( Swl/+) mice and their postnatal dorsal root ganglion (DRG) of surviving Swl/+ mice. The Swl/+ mice could survive for a normal life span, while Swl/Swl could only survive till embryonic (E) 8.5 days. Excessive apoptosis of Swl/+ DRG neurons was revealed during E11.5-E15.5 days, and the peak rate was at E13.5 days. In vitro study of mutated DRG neurons showed impaired retrograde transport of dynein-driven nerve growth factor (NGF). Mitochondria, another dynein-driven cargo, demonstrated much slower retrograde transport velocity in Swl/+ neurons than in wild-type (WT) neurons. Nevertheless, the Swl, Loa, and Cra mutations did not affect homodimerization of DYNC1H1. Conclusion The Swl/Swl mutation of Dync1h1 gene led to embryonic mal-development and lethality, whereas the Swl/+ DRG neurons demonstrated deficient retrograde transport in dynein-driven cargos and excessive apoptosis during mid- to late-developmental stages. The underlying mechanism of the mutation may not be due to impaired homodimerization of DYNC1H1. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
48. Neuronal loss and microgliosis are restricted to the core of Aβ deposits in mouse models of Alzheimer's disease
- Author
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Baian Chen, Jing Lu, Shubo Wang, Fuchuan Xiao, Jing Zhang, Na Wu, and Zitong Yao
- Subjects
Male ,0301 basic medicine ,Aging ,myelin sheath loss ,microglia ,Disease ,Biology ,Microgliosis ,Pathogenesis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,medicine ,Animals ,Humans ,Axon ,Neuroinflammation ,Neurons ,Original Paper ,Amyloid beta-Peptides ,Microglia ,Neurodegeneration ,axon loss ,Original Articles ,Cell Biology ,Alzheimer's disease ,medicine.disease ,Aβ deposits ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Myelin sheath ,neuron loss ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Amyloid‐β (Aβ) deposits, pathologic tau, and neurodegeneration are major pathological hallmarks of Alzheimer's disease (AD). The relationship between neuronal loss and Aβ deposits is one of the fundamental questions in the pathogenesis of AD. However, this relationship is controversial. One main reason for the conflicting results may be the confounding effects of pathologic tau, which often coexists with Aβ deposits in the brains of AD patients. To clarify the relationship between neuronal loss and Aβ deposits, mouse models of AD, which develop abundant Aβ deposits in the aged brain without pathologic tau, were used to examine the co‐localization of NeuN‐positive neurons, NF‐H‐positive axons, MBP‐positive myelin sheaths, and Aβ deposits. Neuronal loss, as measured by decreased staining of the neuronal cell body, axon, and myelin sheath, as well as the IBA‐1‐positive microglia, was significantly increased in the core area of cerebral Aβ deposits, but not in adjacent areas. Furthermore, neuronal loss in the core area of cerebral Aβ deposits was correlated with Aβ deposit size. These results clearly indicate that neuronal loss is restricted to the core of Aβ deposits, and this restricted loss probably occurs because the Aβ deposit attracts microglia, which cluster in the core area where Aβ toxicity and neuroinflammation toxicity are restrained. These findings may contribute to our understanding of the relationship between neuronal loss and Aβ deposits in the absence of pathologic tau., Neuronal loss is restricted to the core of Aβ deposits, and this restricted loss probably occurs because the Aβ deposit attracts microglia, which cluster in the core area where Aβ toxicity and neuroinflammation toxicity are restrained.
- Published
- 2021
49. Neuropathology of Epilepsy
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Dam, Agnete Mouritzen, Pickard, John D., editor, Maira, Giulio, editor, Polkey, Charles E., editor, and Trojanowski, Tomasz, editor
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- 1990
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50. Testing Different Combinations of Acoustic Pressure and Doses of Quinolinic Acid for Induction of Focal Neuron Loss in Mice Using Transcranial Low-Intensity Focused Ultrasound
- Author
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Siqin Huang, Hong Jiang, Edward H. Bertram, Chengde Liao, Yanrong Zhang, Emily Abrams, Frezghi Habte, Kevin S. Lee, Haiyan Zhou, Paul S. Buckmaster, Haibo Qu, Max Wintermark, Li Yuan, and Kim Butts Pauly
- Subjects
Male ,Acoustics and Ultrasonics ,Low dosage ,Biophysics ,Article ,Focused ultrasound ,030218 nuclear medicine & medical imaging ,Neuron loss ,Lesion ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pressure ,otorhinolaryngologic diseases ,medicine ,Animals ,Hippocampus (mythology) ,Radiology, Nuclear Medicine and imaging ,Sound pressure ,Neurons ,Dose-Response Relationship, Drug ,Radiological and Ultrasound Technology ,Brain ,Acoustics ,Quinolinic Acid ,Intensity (physics) ,Disease Models, Animal ,Ultrasonic Waves ,chemistry ,medicine.symptom ,030217 neurology & neurosurgery ,Biomedical engineering ,Quinolinic acid - Abstract
The goal of this study was to test different combinations of acoustic pressure and doses of quinolinic acid (QA) for producing a focal neuronal lesion in the murine hippocampus without causing unwanted damage to adjacent brain structures. Sixty male CD-1 mice were divided into 12 groups that underwent magnetic resonance-guided focused ultrasound at high (0.67 MPa), medium (0.5 MPa) and low (0.33 MPa) acoustic peak negative pressures and received QA at high (0.012 mmol), medium (0.006 mmol) and low (0.003 mmol) dosages. Neuronal loss occurred only when magnetic resonance-guided focused ultrasound with adequate acoustic power (0.67 or 0.5 MPa) was combined with QA. The animals subjected to the highest acoustic power had larger lesions than those treated with medium acoustic power, but two mice had evidence of bleeding. When the intermediate acoustic power was used, medium and high dosages of QA produced lesions larger than those produced by the low dosage.
- Published
- 2019
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