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Background: Microglial cell iron load and inflammatory activation are significant hallmarks of late-stage Alzheimer's disease (AD). In vitro, microglia preferentially upregulate the iron importer, divalent metal transporter 1 (DMT1, gene name Slc11a2) in response to inflammatory stimuli, and excess iron can augment cellular inflammation, suggesting a feed-forward loop between iron import mechanisms and inflammatory signaling. However, it is not understood whether microglial iron import mechanisms directly contribute to inflammatory signaling and chronic disease in vivo. These studies determined the effects of microglial-specific knockdown of Slc11a2 on AD-related cognitive decline and microglial transcriptional phenotype. Methods: In vitro experiments and RT-qPCR were used to assess a role for DMT1 in amyloid-β-associated inflammation. To determine the effects of microglial Slc11a2 knockdown on AD-related phenotypes in vivo, triple-transgenic Cx3cr1Cre−ERT2;Slc11a2flfl;APP/PS1+or – mice were generated and administered corn oil or tamoxifen to induce knockdown at 5–6 months of age. Both sexes underwent behavioral analyses to assess cognition and memory (12–15 months of age). Hippocampal CD11b+ microglia were magnetically isolated from female mice (15–17 months) and bulk RNA-sequencing analysis was conducted. Results: DMT1 inhibition in vitro robustly decreased Aβ-induced inflammatory gene expression and cellular iron levels in conditions of excess iron. In vivo, Slc11a2KDAPP/PS1 female, but not male, mice displayed a significant worsening of memory function in Morris water maze and a fear conditioning assay, along with significant hyperactivity compared to control WT and APP/PS1 mice. Hippocampal microglia from Slc11a2KDAPP/PS1 females displayed significant increases in Enpp2, Ttr, and the iron-export gene, Slc40a1, compared to control APP/PS1 cells. Slc11a2KD cells from APP/PS1 females also exhibited decreased expression of markers associated with subsets of disease-associated microglia (DAMs), such as Apoe, Ctsb, Ly9, Csf1, and Hif1α. Conclusions: This work suggests a sex-specific role for microglial iron import gene Slc11a2 in propagating behavioral and cognitive phenotypes in the APP/PS1 model of AD. These data also highlight an association between loss of a DAM-like phenotype in microglia and cognitive deficits in Slc11a2KDAPP/PS1 female mice. Overall, this work illuminates an iron-related pathway in microglia that may serve a protective role during disease and offers insight into mechanisms behind disease-related sex differences. [ABSTRACT FROM AUTHOR]

Background: Synaptic dysfunction, characterized by synapse loss and structural alterations, emerges as a prominent correlate of cognitive decline in Alzheimer's disease (AD). Actin cytoskeleton, which serves as the structural backbone of synaptic architecture, is observed to be lost from synapses in AD. Actin cytoskeleton loss compromises synaptic integrity, affecting glutamatergic receptor levels, neurotransmission, and synaptic strength. Understanding these molecular changes is crucial for developing interventions targeting synaptic dysfunction, potentially mitigating cognitive decline in AD. Methods: In this study, we investigated the synaptic actin interactome using mass spectrometry in a mouse model of AD, APP/PS1. Our objective was to explore how alterations in synaptic actin dynamics, particularly the interaction between PSD-95 and actin, contribute to synaptic and cognitive impairment in AD. To assess the impact of restoring F-actin levels on synaptic and cognitive functions in APP/PS1 mice, we administered F-actin stabilizing agent, jasplakinolide. Behavioral deficits in the mice were evaluated using the contextual fear conditioning paradigm. We utilized primary neuronal cultures to study the synaptic levels of AMPA and NMDA receptors and the dynamics of PSD-95 actin association. Furthermore, we analyzed postmortem brain tissue samples from subjects with no cognitive impairment (NCI), mild cognitive impairment (MCI), and Alzheimer's dementia (AD) to determine the association between PSD-95 and actin. Results: We found a significant reduction in PSD-95-actin association in synaptosomes from middle-aged APP/PS1 mice compared to wild-type (WT) mice. Treatment with jasplakinolide, an actin stabilizer, reversed deficits in memory recall, restored PSD-95-actin association, and increased synaptic F-actin levels in APP/PS1 mice. Additionally, actin stabilization led to elevated synaptic levels of AMPA and NMDA receptors, enhanced dendritic spine density, suggesting improved neurotransmission and synaptic strength in primary cortical neurons from APP/PS1 mice. Furthermore, analysis of postmortem human tissue with NCI, MCI and AD subjects revealed disrupted PSD-95-actin interactions, underscoring the clinical relevance of our preclinical studies. Conclusion: Our study elucidates disrupted PSD-95 actin interactions across different models, highlighting potential therapeutic targets for AD. Stabilizing F-actin restores synaptic integrity and ameliorates cognitive deficits in APP/PS1 mice, suggesting that targeting synaptic actin regulation could be a promising therapeutic strategy to mitigate cognitive decline in AD. [ABSTRACT FROM AUTHOR]

Abstract Background Synaptic dysfunction, characterized by synapse loss and structural alterations, emerges as a prominent correlate of cognitive decline in Alzheimer’s disease (AD). Actin cytoskeleton, which serves as the structural backbone of synaptic architecture, is observed to be lost from synapses in AD. Actin cytoskeleton loss compromises synaptic integrity, affecting glutamatergic receptor levels, neurotransmission, and synaptic strength. Understanding these molecular changes is crucial for developing interventions targeting synaptic dysfunction, potentially mitigating cognitive decline in AD. Methods In this study, we investigated the synaptic actin interactome using mass spectrometry in a mouse model of AD, APP/PS1. Our objective was to explore how alterations in synaptic actin dynamics, particularly the interaction between PSD-95 and actin, contribute to synaptic and cognitive impairment in AD. To assess the impact of restoring F-actin levels on synaptic and cognitive functions in APP/PS1 mice, we administered F-actin stabilizing agent, jasplakinolide. Behavioral deficits in the mice were evaluated using the contextual fear conditioning paradigm. We utilized primary neuronal cultures to study the synaptic levels of AMPA and NMDA receptors and the dynamics of PSD-95 actin association. Furthermore, we analyzed postmortem brain tissue samples from subjects with no cognitive impairment (NCI), mild cognitive impairment (MCI), and Alzheimer’s dementia (AD) to determine the association between PSD-95 and actin. Results We found a significant reduction in PSD-95-actin association in synaptosomes from middle-aged APP/PS1 mice compared to wild-type (WT) mice. Treatment with jasplakinolide, an actin stabilizer, reversed deficits in memory recall, restored PSD-95-actin association, and increased synaptic F-actin levels in APP/PS1 mice. Additionally, actin stabilization led to elevated synaptic levels of AMPA and NMDA receptors, enhanced dendritic spine density, suggesting improved neurotransmission and synaptic strength in primary cortical neurons from APP/PS1 mice. Furthermore, analysis of postmortem human tissue with NCI, MCI and AD subjects revealed disrupted PSD-95-actin interactions, underscoring the clinical relevance of our preclinical studies. Conclusion Our study elucidates disrupted PSD-95 actin interactions across different models, highlighting potential therapeutic targets for AD. Stabilizing F-actin restores synaptic integrity and ameliorates cognitive deficits in APP/PS1 mice, suggesting that targeting synaptic actin regulation could be a promising therapeutic strategy to mitigate cognitive decline in AD.

A significant proportion of brains with Alzheimer's disease pathology are obtained from patients that were cognitively normal, suggesting that differences within the brains of these individuals made them resilient to the disease. Here, we describe recent approaches that specifically increase synaptic resilience, as loss of synapses is considered to be the first change in the brains of Alzheimer's patients. We start by discussing studies showing benefit from increased expression of neurotrophic factors and protective genes. Methods that effectively make dendritic spines stronger, specifically by acting through actin network proteins, scaffolding proteins and inhibition of phosphatases are described next. Importantly, the therapeutic strategies presented in this review tackle Alzheimer's disease not by targeting plaques and tangles, but instead by making synapses resilient to the pathology associated with Alzheimer's disease, which has tremendous potential.

INTRODUCTION: Early‐life stress (ES) increases the risk for Alzheimer's disease (AD). We and others have shown that ES aggravates amyloid‐beta (Aβ) pathology and promotes cognitive dysfunction in APP/PS1 mice, but underlying mechanisms remain unclear. METHODS: We studied how ES affects the hippocampal synaptic proteome in wild‐type (WT) and APP/PS1 mice at early and late pathological stages, and validated hits using electron microscopy and immunofluorescence. RESULTS: The hippocampal synaptosomes of both ES‐exposed WT and early‐stage APP/PS1 mice showed a relative decrease in actin dynamics‐related proteins and a relative increase in mitochondrial proteins. ES had minimal effects on older WT mice, while strongly affecting the synaptic proteome of advanced stage APP/PS1 mice, particularly the expression of astrocytic and mitochondrial proteins. DISCUSSION: Our data show that ES and amyloidosis share pathogenic pathways involving synaptic mitochondrial dysfunction and lipid metabolism, which may underlie the observed impact of ES on the trajectory of AD. [ABSTRACT FROM AUTHOR]

Abstract Alzheimer’s disease (AD) is a multifactorial, rapidly progressing neurodegenerative disorder. As the exact cause of the disease is still unclear, the drug development is very challenging. This review encompasses the commonly used AD models involving various chemicals, heavy metals and endogenous substances induced models and the transgenic models. It also provides insight into the reliable emerging models of AD that may overcome the shortcomings associated with available models. Chemicals like streptozotocin, scopolamine, colchicine and okadaic acid render the animal susceptible to neuroinflammation and oxidative stress induced neurodegeneration along with amyloid-β deposition and tau hyperphosphorylation. Similarly, endogenous substances like acrolein and amyloid-β 1–42 are efficient in inducing the major pathologies of AD. Heavy metals like aluminum and fluoride and mixture of these have been reported to induce neurotoxicity therefore are used as animal models for AD. Transgenic models developed as a result of knock-in or knock-out of certain genes associated with AD including PDAPP, APP23, Tg2576, APP/PS1, 3 × Tg and 5 × FAD have also been incorporated in this study. Further, emerging and advanced pathomimetic models of AD are provided particular interest here which will add on to the current knowledge of animal models and may aid in the drug development process and deepen our understanding related to AD pathogenesis. These newly discovered models include oAβ25-35 model, transgenic model expressing 82-kDa ChAT, oDGal mouse and APP knock-in rat. This study may aid in the selection of suitable model for development of novel potent therapeutics and for exploring detailed pathogenic mechanism of AD. Graphical abstract

Brain‐derived extracellular vesicles (EVs) play an active role in Alzheimer's disease (AD), relaying important physiological information about their host tissues. The internal cargo of EVs is protected from degradation, making EVs attractive AD biomarkers. However, it is unclear how circulating EVs relate to EVs isolated from disease‐vulnerable brain regions. We developed a novel method for collecting EVs from the hippocampal interstitial fluid (ISF) of live mice. EVs (EVISF) were isolated via ultracentrifugation and characterized by nanoparticle tracking analysis, immunogold labelling, and flow cytometry. Mass spectrometry and proteomic analyses were performed on EVISF cargo. EVISF were 40–150 nm in size and expressed CD63, CD9, and CD81. Using a model of cerebral amyloidosis (e.g., APPswe, PSEN1dE9 mice), we found protein concentration increased but protein diversity decreased with Aβ deposition. Genotype, age, and Aβ deposition modulated proteostasis‐ and immunometabolic‐related pathways. Changes in the microglial EVISF proteome were sexually dimorphic and associated with a differential response of plaque associated microglia. We found that female APP/PS1 mice have more amyloid plaques, less plaque associated microglia, and a less robust‐ and diverse‐ EVISF microglial proteome. Thus, in vivo microdialysis is a novel technique for collecting EVISF and offers a unique opportunity to explore the role of EVs in AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a multifactorial, rapidly progressing neurodegenerative disorder. As the exact cause of the disease is still unclear, the drug development is very challenging. This review encompasses the commonly used AD models involving various chemicals, heavy metals and endogenous substances induced models and the transgenic models. It also provides insight into the reliable emerging models of AD that may overcome the shortcomings associated with available models. Chemicals like streptozotocin, scopolamine, colchicine and okadaic acid render the animal susceptible to neuroinflammation and oxidative stress induced neurodegeneration along with amyloid-β deposition and tau hyperphosphorylation. Similarly, endogenous substances like acrolein and amyloid-β 1–42 are efficient in inducing the major pathologies of AD. Heavy metals like aluminum and fluoride and mixture of these have been reported to induce neurotoxicity therefore are used as animal models for AD. Transgenic models developed as a result of knock-in or knock-out of certain genes associated with AD including PDAPP, APP23, Tg2576, APP/PS1, 3 × Tg and 5 × FAD have also been incorporated in this study. Further, emerging and advanced pathomimetic models of AD are provided particular interest here which will add on to the current knowledge of animal models and may aid in the drug development process and deepen our understanding related to AD pathogenesis. These newly discovered models include oAβ25-35 model, transgenic model expressing 82-kDa ChAT, oDGal mouse and APP knock-in rat. This study may aid in the selection of suitable model for development of novel potent therapeutics and for exploring detailed pathogenic mechanism of AD. [ABSTRACT FROM AUTHOR]

Transgenic models of familial Alzheimer's disease (AD) serve as valuable tools for probing the molecular mechanisms associated with amyloid-beta (Aβ)-induced pathology. In this meta-analysis, we sought to evaluate levels of phosphorylated tau (p-tau) and explore potential age-related variations in tau hyperphosphorylation, within mouse models of AD. The PubMed and Scopus databases were searched for studies measuring soluble p-tau in 5xFAD, APPswe/PSEN1de9, J20 and APP23 mice. Data were extracted and analyzed using standardized procedures. For the 5xFAD model, the search yielded 36 studies eligible for meta-analysis. Levels of p-tau were higher in 5xFAD mice relative to control, a difference that was evident in both the carboxy-terminal (CT) and proline-rich (PR) domains of tau. Age negatively moderated the relationship between genotype and CT phosphorylated tau in studies using hybrid mice, female mice, and preparations from the neocortex. For the APPswe/PSEN1de9 model, the search yielded 27 studies. Analysis showed tau hyperphosphorylation in transgenic vs. control animals, evident in both the CT and PR regions of tau. Age positively moderated the relationship between genotype and PR domain phosphorylated tau in the neocortex of APPswe/PSEN1de9 mice. A meta-analysis was not performed for the J20 and APP23 models, due to the limited number of studies measuring p-tau levels in these mice (

Abstract Background The existence of an interconnected mechanism between cognitive disorders and periodontitis has been confirmed by mounting evidence. However, the role of age or sex differences in this mechanism has been less studied. This study aims to investigate sex and age differences in the characterization of periodontal bone tissue, immune state and cognitive function in amyloid precursor protein/presenilin 1(APP/PS1) murine model of Alzheimer’s disease (AD). Methods Three- and twelve-month-old male and female APP/PS1 transgenic mice and wild-type (WT) littermates were used in this study. The Morris water maze (MWM) was used to assess cognitive function. The bone microarchitecture of the posterior maxillary alveolar bone was evaluated by microcomputed tomography (micro-CT). Pathological changes in periodontal bone tissue were observed by histological chemistry. The proportions of helper T cells1 (Th1), Th2, Th17 and regulatory T cells (Tregs) in the peripheral blood mononuclear cells (PBMCs) and brain samples were assessed by flow cytometry. Results The learning ability and spatial memory of 12-month-old APP/PS1 mice was severely damaged. The changes in cognitive function were only correlated with age and genotype, regardless of sex. The 12-month-old APP/PS1 female mice exhibited markedly periodontal bone degeneration, evidenced by the decreased bone volume/total volume (BV/TV), trabecular thickness (Tb.Th), and bone mineral density (BMD), and the increased trabecular separation (Tb.Sp). The altered periodontal bone microarchitecture was associated with genotype, age and females. The flow cytometry data showed the increased Th1 and Th17 cells and the decreased Th2 cells in the brain and PBMC samples of 12-month-old APP/PS1 mice, compared to age- and sex-matched WT mice. However, there was no statistical correlation between age or sex and this immune state. Conclusions Our data emphasize that age and sex are important variables to consider in evaluating periodontal bone tissue of APP/PS1 mice, and the cognitive impairment is more related to age. In addition, immune dysregulation (Th1, Th2, and Th17 cells) was found in the brain tissue and PBMCs of APP/PS1 mice, but this alteration of immune state was not statistically correlated with sex or age.

Abstract Brain‐derived extracellular vesicles (EVs) play an active role in Alzheimer's disease (AD), relaying important physiological information about their host tissues. The internal cargo of EVs is protected from degradation, making EVs attractive AD biomarkers. However, it is unclear how circulating EVs relate to EVs isolated from disease‐vulnerable brain regions. We developed a novel method for collecting EVs from the hippocampal interstitial fluid (ISF) of live mice. EVs (EVISF) were isolated via ultracentrifugation and characterized by nanoparticle tracking analysis, immunogold labelling, and flow cytometry. Mass spectrometry and proteomic analyses were performed on EVISF cargo. EVISF were 40–150 nm in size and expressed CD63, CD9, and CD81. Using a model of cerebral amyloidosis (e.g., APPswe, PSEN1dE9 mice), we found protein concentration increased but protein diversity decreased with Aβ deposition. Genotype, age, and Aβ deposition modulated proteostasis‐ and immunometabolic‐related pathways. Changes in the microglial EVISF proteome were sexually dimorphic and associated with a differential response of plaque associated microglia. We found that female APP/PS1 mice have more amyloid plaques, less plaque associated microglia, and a less robust‐ and diverse‐ EVISF microglial proteome. Thus, in vivo microdialysis is a novel technique for collecting EVISF and offers a unique opportunity to explore the role of EVs in AD.

Alzheimer's disease (AD) is a progressive brain disorder characterized by extracellular amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles formed by hyperphosphorylated Tau protein and neuroinflammation. Previous research has shown that obesity and type 2 diabetes mellitus, underlined by insulin resistance (IR), are risk factors for neurodegenerative disorders. In this study, obesity-induced peripheral and central IR and inflammation were studied in relation to AD-like pathology in the brains and periphery of APP/PS1 mice, a model of Aβ pathology, fed a high-fat diet (HFD). APP/PS1 mice and their wild-type controls fed either a standard diet or HFD were characterized at the ages of 3, 6 and 10 months by metabolic parameters related to obesity via mass spectroscopy, nuclear magnetic resonance, immunoblotting and immunohistochemistry to quantify how obesity affected AD pathology. The HFD induced substantial peripheral IR leading to central IR. APP/PS1-fed HFD mice had more pronounced IR, glucose intolerance and liver steatosis than their WT controls. The HFD worsened Aβ pathology in the hippocampi of APP/PS1 mice and significantly supported both peripheral and central inflammation. This study reveals a deleterious effect of obesity-related mild peripheral inflammation and prediabetes on the development of Aβ and Tau pathology and neuroinflammation in APP/PS1 mice. [ABSTRACT FROM AUTHOR]

Severe cognitive decline is a hallmark of Alzheimer's disease (AD). In addition to gray matter loss, significant white matter pathology has been identified in AD patients. Here, we characterized the dynamics of myelin generation and loss in the APP/PS1 mouse model of AD. Unexpectedly, we observed a dramatic increase in the rate of new myelin formation in APP/PS1 mice, reminiscent of the robust oligodendroglial response to demyelination. Despite this increase, overall levels of myelination are decreased in the cortex and hippocampus of APP/PS1 mice and postmortem AD tissue. Genetically or pharmacologically enhancing myelin renewal, by oligodendroglial deletion of the muscarinic M1 receptor or systemic administration of the pro-myelinating drug clemastine, improved the performance of APP/PS1 mice in memory-related tasks and increased hippocampal sharp wave ripples. Taken together, these results demonstrate the potential of enhancing myelination as a therapeutic strategy to alleviate AD-related cognitive impairment.

Neuronal synchronization at gamma frequency (30-100 Hz: γ) is impaired in early-stage Alzheimer's disease (AD) patients and AD models. Oligomeric Aβ1-42 caused a concentration-dependent reduction of γ-oscillation strength and regularity while increasing its frequency. The mTOR1 inhibitor rapamycin prevented the Aβ1-42-induced suppression of γ-oscillations, whereas the mTOR activator leucine mimicked the Aβ1-42-induced suppression. Activation of the downstream kinase S6K1, but not inhibition of eIF4E, was required for the Aβ1-42-induced suppression. The involvement of the mTOR/S6K1 signaling in the Aβ1-42-induced suppression was confirmed in Aβ-overexpressing APP/PS1 mice, where inhibiting mTOR or S6K1 restored degraded γ-oscillations. To assess the network changes that may underlie the mTOR/S6K1 mediated γ-oscillation impairment in AD, we tested the effect of Aβ1-42 on IPSCs and EPSCs recorded in pyramidal neurons. Aβ1-42 reduced EPSC amplitude and frequency and IPSC frequency, which could be prevented by inhibiting mTOR or S6K1. These experiments indicate that in early AD, oligomer Aβ1-42 impairs γ-oscillations by reducing inhibitory interneuron activity by activating the mTOR/S6K1 signaling pathway, which may contribute to early cognitive decline and provides new therapeutic targets. [ABSTRACT FROM AUTHOR]

Therapeutic approaches providing effective medication for Alzheimer's disease (AD) patients after disease onset are urgently needed. Previous studies in AD mouse models and in humans suggested that physical exercise or changed lifestyle can delay AD-related synaptic and memory dysfunctions when treatment started in juvenile animals or in elderly humans before onset of disease symptoms. However, a pharmacological treatment that can reverse memory deficits in AD patients was thus far not identified. Importantly, AD disease-related dysfunctions have increasingly been associated with neuro-inflammatory mechanisms and searching for anti-inflammatory medication to treat AD seems promising. Like for other diseases, repurposing of FDA-approved drugs for treatment of AD is an ideally suited strategy to reduce the time to bring such medication into clinical practice. Of note, the sphingosine-1-phosphate analogue fingolimod (FTY720) was FDA-approved in 2010 for treatment of multiple sclerosis patients. It binds to the five different isoforms of Sphingosine-1-phosphate receptors (S1PRs) that are widely distributed across human organs. Interestingly, recent studies in five different mouse models of AD suggest that FTY720 treatment, even when starting after onset of AD symptoms, can reverse synaptic deficits and memory dysfunction in these AD mouse models. Furthermore, a very recent multi-omics study identified mutations in the sphingosine/ceramide pathway as a risk factor for sporadic AD, suggesting S1PRs as promising drug target in AD patients. Therefore, progressing with FDA-approved S1PR modulators into human clinical trials might pave the way for these potential disease modifying anti-AD drugs. [ABSTRACT FROM AUTHOR]

Inhibition of phosphodiesterase 4D (PDE4D) enzymes has been investigated as therapeutic strategy to treat memory problems in Alzheimer’s disease (AD). Although PDE4D inhibitors are effective in enhancing memory processes in rodents and humans, severe side effects may hamper their clinical use. PDE4D enzymes comprise different isoforms, which, when targeted specifically, can increase treatment efficacy and safety. The function of PDE4D isoforms in AD and in molecular memory processes per se has remained unresolved. Here, we report the upregulation of specific PDE4D isoforms in transgenic AD mice and hippocampal neurons exposed to amyloid-β. Furthermore, by means of pharmacological inhibition and CRISPR-Cas9 knockdown, we show that the long-form PDE4D3, -D5, -D7, and -D9 isoforms regulate neuronal plasticity and convey resilience against amyloid-β in vitro. These results indicate that isoform-specific, next to non-selective, PDE4D inhibition is efficient in promoting neuroplasticity in an AD context. Therapeutic effects of non-selective PDE4D inhibitors are likely achieved through actions on long isoforms. Future research should identify which long PDE4D isoforms should be specifically targeted in vivo to both improve treatment efficacy and reduce side effects. [ABSTRACT FROM AUTHOR]

This study examined the effect of curcumin on pathological manifestations and clearance of amyloid β peptide (Aβ) in the hippocampus of 8-month-old transgenic APP/PS1 mice with inherent Alzheimer's disease. APP/PS1 mice and the age-matched wild-type controls were subjected to 3 behavioral tests: open field, new object recognition, and Morris water maze. Expression of Aβ, APP, CTF, BACE1, IDE, NEP, and LRP1 proteins in the extracted hippocampal tissue was evaluated by Western blotting. The distribution and the quantity of amyloid plaques and the spread of microglia in the hippocampus were determined by immunofluorescence. The contents of Aβ40 and Aβ42 in the hippocampus were assayed and analyzed on Simoa HD-1 analyzer. The proteins interacting with Aβ in the hippocampus of APP/PS1 mice were detected by co-immunoprecipitation. Curcumin significantly reduced motor hyperactivity in the open-field test, improved short-term recognition memory, spatial learning, and reference memory in APP/PS1 mice. In the hippocampus of APP/PS1 mice, curcumin significantly diminished the elevated Aβ levels and inhibited microglia proliferation. At the same time, curcumin had no effect on Aβ production, extracellular enzymatic hydrolysis, and LRP1-mediated outward transport, but enhanced Aβ clearance by activation of the intracellular ubiquitin-proteasome system and related peripheral mechanisms. Thus, curcumin improves the learning and memory abilities of APP/PS1 mice and reduces the pathological accumulation of Aβ in the brain. [ABSTRACT FROM AUTHOR]

Background: The existence of an interconnected mechanism between cognitive disorders and periodontitis has been confirmed by mounting evidence. However, the role of age or sex differences in this mechanism has been less studied. This study aims to investigate sex and age differences in the characterization of periodontal bone tissue, immune state and cognitive function in amyloid precursor protein/presenilin 1(APP/PS1) murine model of Alzheimer's disease (AD). Methods: Three- and twelve-month-old male and female APP/PS1 transgenic mice and wild-type (WT) littermates were used in this study. The Morris water maze (MWM) was used to assess cognitive function. The bone microarchitecture of the posterior maxillary alveolar bone was evaluated by microcomputed tomography (micro-CT). Pathological changes in periodontal bone tissue were observed by histological chemistry. The proportions of helper T cells1 (Th1), Th2, Th17 and regulatory T cells (Tregs) in the peripheral blood mononuclear cells (PBMCs) and brain samples were assessed by flow cytometry. Results: The learning ability and spatial memory of 12-month-old APP/PS1 mice was severely damaged. The changes in cognitive function were only correlated with age and genotype, regardless of sex. The 12-month-old APP/PS1 female mice exhibited markedly periodontal bone degeneration, evidenced by the decreased bone volume/total volume (BV/TV), trabecular thickness (Tb.Th), and bone mineral density (BMD), and the increased trabecular separation (Tb.Sp). The altered periodontal bone microarchitecture was associated with genotype, age and females. The flow cytometry data showed the increased Th1 and Th17 cells and the decreased Th2 cells in the brain and PBMC samples of 12-month-old APP/PS1 mice, compared to age- and sex-matched WT mice. However, there was no statistical correlation between age or sex and this immune state. Conclusions: Our data emphasize that age and sex are important variables to consider in evaluating periodontal bone tissue of APP/PS1 mice, and the cognitive impairment is more related to age. In addition, immune dysregulation (Th1, Th2, and Th17 cells) was found in the brain tissue and PBMCs of APP/PS1 mice, but this alteration of immune state was not statistically correlated with sex or age. [ABSTRACT FROM AUTHOR]

A significant proportion of brains with Alzheimer's disease pathology are obtained from patients that were cognitively normal, suggesting that differences within the brains of these individuals made them resilient to the disease. Here, we describe recent approaches that specifically increase synaptic resilience, as loss of synapses is considered to be the first change in the brains of Alzheimer's patients. We start by discussing studies showing benefit from increased expression of neurotrophic factors and protective genes. Methods that effectively make dendritic spines stronger, specifically by acting through actin network proteins, scaffolding proteins and inhibition of phosphatases are described next. Importantly, the therapeutic strategies presented in this review tackle Alzheimer's disease not by targeting plaques and tangles, but instead by making synapses resilient to the pathology associated with Alzheimer's disease, which has tremendous potential. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by synaptic failure and neuronal loss. Recently, we demonstrated that artemisinins restored the levels of key proteins of inhibitory GABAergic synapses in the hippocampus of APP/PS1 mice, a model of cerebral amyloidosis. In the present study, we analyzed the protein levels and subcellular localization of α2 and α3 subunits of GlyRs, indicated as the most abundant receptor subtypes in the mature hippocampus, in early and late stages of AD pathogenesis, and upon treatment with two different doses of artesunate (ARS). Immunofluorescence microscopy and Western blot analysis demonstrated that the protein levels of both α2 and α3 GlyRs are considerably reduced in the CA1 and the dentate gyrus of 12-month-old APP/PS1 mice when compared to WT mice. Notably, treatment with low-dose ARS affected GlyR expression in a subunit-specific way; the protein levels of α3 GlyR subunits were rescued to about WT levels, whereas that of α2 GlyRs were not affected significantly. Moreover, double labeling with a presynaptic marker indicated that the changes in GlyR α3 expression levels primarily involve extracellular GlyRs. Correspondingly, low concentrations of artesunate (≤1 µM) also increased the extrasynaptic GlyR cluster density in hAPPswe-transfected primary hippocampal neurons, whereas the number of GlyR clusters overlapping presynaptic VIAAT immunoreactivities remained unchanged. Thus, here we provide evidence that the protein levels and subcellular localization of α2 and α3 subunits of GlyRs show regional and temporal alterations in the hippocampus of APP/PS1 mice that can be modulated by the application of artesunate. [ABSTRACT FROM AUTHOR]

Introduction: Synapse loss is one of the hallmarks of Alzheimer's disease (AD) and is associated with cognitive decline. In this study, we tested [18F]SDM-16, a novel metabolically stable SV2A PET imaging probe, in the transgenic APPswe/PSldE9 (APP/PS1) mouse model of AD and age-matched wild-type (WT) mice at 12 months of age. Methods: Based on previous preclinical PET imaging studies using [11-C]UCB-J and [18F]SynVesT-l in the same strain animals, we used the simplified reference tissue model (SRTM), with brain stem as the pseudo reference region to calculate distribution volume ratios (DVRs). Results: To simplify and streamline the quantitative analysis, we compared the standardized uptake value ratios (SUVRs) from different imaging windows to DVRs and found that the averaged SUVRs from 60-90 min post-injection (p./.) are most consistent with the DVRs. Thus, we used averaged SUVRs from 60-90 min for group comparisons and found statistically significant differences in the tracer uptake in different brain regions, e.g., hippocampus (p = 0.001), striatum (p = 0.002), thalamus (p = 0.003), and cingulate cortex (p = 0.0003). Conclusions: In conclusion, [18F]SDM-16 was used to detect decreased SV2A levels in the brain of APP/PS1 AD mouse model at one year old. Our data suggest that [18F]SDM-16 has similar statistical power in detecting the synapse loss in APP/PS1 mice as [1:1-C]UCB-J and [18F]SynVesT-1, albeit later imaging window (60-90 min p./.) is needed when SUVR is used as a surrogate for DVR for [18F]SDM-16 due to its slower brain kinetics. [ABSTRACT FROM AUTHOR]

Introduction: Astrocyte-synapse bi-directional communication is required for neuronal development and synaptic plasticity. Astrocytes structurally interact with synapses using their distal processes also known as leaflets or perisynaptic astrocytic processes (PAPs). We recently showed that these PAPs are retracted from hippocampal synapses, and involved in the consolidation of fear memory. However, whether astrocytic synaptic coverage is affected when memory is impaired is unknown. Methods: Here, we describe in detail an electron microscopy method that makes use of a large number of 2D images to investigate structural astrocyte-synapse interaction in paraformaldehyde fixed brain tissue of mice. Results and discussion: We show that fear memory-induced synaptic activation reduces the interaction between the PAPs and the presynapse, but not the postsynapse, accompanied by retraction of the PAP tip from the synaptic cleft. Interestingly, this retraction is absent in the APP/PS1 mouse model of Alzheimer’s disease, supporting the concept that alterations in astrocyte-synapse coverage contribute to memory processing. [ABSTRACT FROM AUTHOR]

• Microgliosis coincides with increased soluble Aβ 42 levels in APP/PS1mice. • Reactivity of microglia is driving early AD progression in APP/PS1 mice. • Therapeutic inhibition of microgliosis is most effective before its onset. Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, the neuropathological formation of amyloid-beta (Aβ) plaques and neurofibrillary tangles. The best cellular correlates of the early cognitive deficits in AD patients are synapse loss and gliosis. In particular, it is unclear whether the activation of microglia (microgliosis) has a neuroprotective or pathological role early in AD. Here we report that microgliosis is an early mediator of synaptic dysfunction and cognitive impairment in APP/PS1 mice, a mouse model of increased amyloidosis. We found that the appearance of microgliosis, synaptic dysfunction and behavioral impairment coincided with increased soluble Aβ 42 levels, and occurred well before the presence of Aβ plaques. Inhibition of microglial activity by treatment with minocycline (MC) reduced gliosis, synaptic deficits and cognitive impairments at early pathological stages and was most effective when provided preventive, i.e., before the onset of microgliosis. Interestingly, soluble Aβ levels or Aβ plaques deposition were not affected by preventive MC treatment at an early pathological stage (4 months) whereas these were reduced upon treatment at a later stage (6 months). In conclusion, this study demonstrates the importance of early-stage prevention of microgliosis on the development of cognitive impairment in APP/PS1 mice, which might be clinically relevant in preventing memory loss and delaying AD pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Olfactory decline is an indicator of early-stage Alzheimer's disease (AD). Although the anterior piriform cortex (aPC) is an important brain area involved in processing olfactory input, little is known about how its neuronal activity is affected in early-stage AD.Objective: To elucidate whether odor-induced electrophysiological responses are altered in the aPC of 3-5-month-old APP/PS1 mice.Methods: Using head-fixed multi-channel recording techniques in APP/PS1 AD mouse model to uncover potential aberrance of the aPC neuronal firing and local field potential (LFP) in response to vanillin.Results: We show that the firing rate of aPC neurons evoked by vanillin is significantly reduced in conscious APP/PS1 mice. LFP analysis demonstrates reduced low- and high-gamma (γlow,γhigh) oscillations during both the baseline and odor stimulation periods in APP/PS1 mice. Moreover, according to spike-field coherence (SFC) analysis, APP/PS1 mice show decreased coherence between odor-evoked spikes and γlow rhythms, while the coherence with γhigh rhythms and the ΔSFC of the oscillations is unaffected. Furthermore, APP/PS1 mice show reduced phase-locking strength in the baseline period, such that there is no difference between baseline and odor-stimulation conditions. This contrasts markedly with wild type mice, where phase-locking strength decreases on stimulation.Conclusion: The abnormalities in both the neuronal and oscillatory activities of the aPC may serve as electrophysiological indicators of underlying olfactory decline in early AD. [ABSTRACT FROM AUTHOR]

Abstract Soluble amyloid precursor protein-alpha (sAPPα) is a regulator of neuronal and memory mechanisms, while also having neurogenic and neuroprotective effects in the brain. As adult hippocampal neurogenesis is impaired in Alzheimer’s disease, we tested the hypothesis that sAPPα delivery would rescue adult hippocampal neurogenesis in an APP/PS1 mouse model of Alzheimer’s disease. An adeno-associated virus-9 (AAV9) encoding murine sAPPα was injected into the hippocampus of 8-month-old wild-type and APP/PS1 mice, and later two different thymidine analogues (XdU) were systemically injected to label adult-born cells at different time points after viral transduction. The proliferation of adult-born cells, cell survival after eight weeks, and cell differentiation into either neurons or astrocytes was studied. Proliferation was impaired in APP/PS1 mice but was restored to wild-type levels by viral expression of sAPPα. In contrast, sAPPα overexpression failed to rescue the survival of XdU+-labelled cells that was impaired in APP/PS1 mice, although it did cause a significant increase in the area density of astrocytes in the granule cell layer across both genotypes. Finally, viral expression of sAPPα reduced amyloid-beta plaque load in APP/PS1 mice in the dentate gyrus and somatosensory cortex. These data add further evidence that increased levels of sAPPα could be therapeutic for the cognitive decline in AD, in part through restoration of the proliferation of neural progenitor cells in adults.

IntroductionSynapse loss is one of the hallmarks of Alzheimer's disease (AD) and is associated with cognitive decline. In this study, we tested [18F]SDM-16, a novel metabolically stable SV2A PET imaging probe, in the transgenic APPswe/PS1dE9 (APP/PS1) mouse model of AD and age-matched wild-type (WT) mice at 12 months of age.MethodsBased on previous preclinical PET imaging studies using [11C]UCB-J and [18F]SynVesT-1 in the same strain animals, we used the simplified reference tissue model (SRTM), with brain stem as the pseudo reference region to calculate distribution volume ratios (DVRs).ResultsTo simplify and streamline the quantitative analysis, we compared the standardized uptake value ratios (SUVRs) from different imaging windows to DVRs and found that the averaged SUVRs from 60–90 min post-injection (p.i.) are most consistent with the DVRs. Thus, we used averaged SUVRs from 60–90 min for group comparisons and found statistically significant differences in the tracer uptake in different brain regions, e.g., hippocampus (p = 0.001), striatum (p = 0.002), thalamus (p = 0.003), and cingulate cortex (p = 0.0003).ConclusionsIn conclusion, [18F]SDM-16 was used to detect decreased SV2A levels in the brain of APP/PS1 AD mouse model at one year old. Our data suggest that [18F]SDM-16 has similar statistical power in detecting the synapse loss in APP/PS1 mice as [11C]UCB-J and [18F]SynVesT-1, albeit later imaging window (60–90 min p.i.) is needed when SUVR is used as a surrogate for DVR for [18F]SDM-16 due to its slower brain kinetics.

Alzheimer's disease (AD) has become a major public health problem affecting the elderly population, and there is currently no effective treatment. Although the pathogenesis of AD is unclear, neurotoxicity induced by oxidative stress plays an important role in the progression of AD. Ginseng, the root and rhizome of Panax ginseng C. A. Meyer, is used not only as an herbal medicine but also as a functional food to support bodily functions. Ginsenoside Rk3 (Rk3), the main bioactive component in ginseng, has a strong antioxidant effect and has not been reported in AD. In this study, we showed that Rk3 improved neuronal apoptosis, decreased intracellular reactive oxygen species (ROS) production and restored mitochondrial membrane potential in PC12 and primary neuronal cells. In vivo, we found that Rk3 improved spatial learning and memory deficit in precursor protein (APP)/presenilin 1 (PS1) double transgenic mouse model of AD. Additionally, Rk3 increases glutathione reductase (GSH) and superoxide dismutase (SOD) levels while inhibits malondialdehyde (MDA) production, apoptosis and activation of glial cells in APP/PS1 mice. Mechanistically, we found that the protective effect of Rk3 is in correlation with the activation of AMPK/Nrf2 signaling pathway. In conclusion, the findings of this study provide support for Rk3 as a new strategy for the treatment of AD.

Some researchers and clinics have reported that non-drug treatments for Alzheimer disease (AD) such as electrical stimulation, light stimulation, music stimulation, laser stimulation, and transcranial magnetic stimulation may have beneficial treatment effects. Following these findings, in this study, we performed multimodel physical stimulation on APP/PS1 mice using visible light, music with a γ rhythm, and an infrared laser. And the effects of physical stimulation on APP/PS1 mice were evaluated by behavioral analysis, the content of amyloid (Aβ40 and Aβ42), and NISSL staining of hippocampal tissue slices. The results of subsequent behavioral and tissue analyses showed that the multi-model physical stimulations could relieve APP/PS1 mice's dementia symptoms, such as the behavior ability, the content of Aβ40 and Aβ42 in the hippocampal tissue suspension, and Nissl staining for hippocampal tissue analyses.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, tightly related with microglia phenotypic polarization, which finally results in the stimulation of β-amyloid peptides (Aβ) and promotion of phagocytosis of neuronal synaptic structures. Thus, constructing drug system to reverse microglia phenotypic polarization is highly desired for AD therapy. In this study, we developed a nano delivery system (denoted as M@CA@GP NPs) by loading aspirin curcumin ester (CA) on the graphene oxide quantum dots (GOQDs) for AD therapy. With the modification of hybrid cell membrane, this nanoconjugate can efficiently deliver drugs to the brain and regulate the inflammatory microenvironment to improve learning and memory. Moreover, this targeting strategy exhibits the ability of regulating the microglial cell phenotype, promoting Aβ phagocytosis, and maintaining synaptic plasticity with prolonged circulation time and high biocompatibility. Taken together, our results demonstrate that the M@CA@GP NPs can alleviate glial cell activation, decrease Aβ burden, and eventually enhance cognitive functions in APPswe/PSEN1dE9 model mice. These results indicate that M@CA@GP NPs can be a promising therapeutic agent for the treatment of AD.

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder with a complex pathophysiology. Type 2 diabetes (T2D) is a strong risk factor for AD that shares similar abnormal features including metabolic dysregulation and brain pathology such as amyloid and/or Tau deposits. Emerging evidence suggests that circulating branched-chain amino acids (BCAAs) are associated with T2D. While excess BCAAs are shown to be harmful to neurons, its connection to AD is poorly understood. Here we show that individuals with AD have elevated circulating BCAAs and their metabolites compared to healthy individuals, and that a BCAA metabolite is correlated with the severity of dementia. APPSwe mouse model of AD also displayed higher plasma BCAAs compared to controls. In pursuit of understanding a potential causality, BCAA supplementation to HT-22 neurons was found to reduce genes critical for neuronal health while increasing phosphorylated Tau. Moreover, restricting BCAAs from diet delayed cognitive decline and lowered AD-related pathology in the cortex and hippocampus in APP/PS1 mice. BCAA restriction for two months was sufficient to correct glycemic control and increased/restored dopamine that were severely reduced in APP/PS1 controls. Treating 5xFAD mice that show early brain pathology with a BCAA-lowering compound recapitulated the beneficial effects of BCAA restriction on brain pathology and neurotransmitters including norepinephrine and serotonin. Collectively, this study reveals a positive association between circulating BCAAs and AD. Our findings suggest that BCAAs impair neuronal functions whereas BCAA-lowering alleviates AD-related pathology and cognitive decline, thus establishing a potential causal link between BCAAs and AD progression. [ABSTRACT FROM AUTHOR]

Objective: Epileptic spikes and seizures seem present early in the disease process of Alzheimer's disease (AD). However, it is unclear how soluble and insoluble amyloid beta (Aβ) and tau proteins affect seizure development in vivo. We aim to contribute to this field by assessing the vulnerability to 6 Hz corneal kindling of young female mice from two well‐characterized transgenic AD models and by testing their responsiveness to selected antiseizure drugs (ASDs). Methods: We used 7‐week‐old triple transgenic (3xTg) mice that have both amyloid and tau mutations, and amyloid precursor protein Swedish/presenillin 1 dE9 (APP/PS1) mice, bearing only amyloid‐related mutations. We assessed the absence of plaques via immunohistochemistry and analyzed the concentrations of both soluble and insoluble forms of Aβ1–42 and total tau (t‐tau) in brain hippocampal and prefrontal cortical tissue. Seven‐week‐old mice of the different genotypes were subjected to the 6 Hz corneal kindling model. After kindling acquisition, we tested the anticonvulsant effects of three marketed ASDs (levetiracetam, brivaracetam, and lamotrigine) in fully kindled mice. Results: No Aβ plaques were present in either genotype. Soluble Aβ1–42 levels were increased in both AD genotypes, whereas insoluble Aβ1–42 concentrations were only elevated in APP/PS1 mice compared with their respective controls. Soluble and insoluble forms of t‐tau were increased in 3xTg mice only. 3xTg and APP/PS1 mice displayed more severe seizures induced by 6 Hz corneal kindling from the first stimulation onward and were more rapidly kindled compared with control mice. In fully kindled AD mice, ASDs had less‐pronounced anticonvulsive effects compared with controls. Significance: Mutations increasing Aβ only or both Aβ and tau in the brain enhance susceptibility for seizures and kindling in mice. The effect of ASDs on seizures measured by the Racine scale is less pronounced in both investigated AD models and suggests that seizures of young AD mice are more difficult to treat. [ABSTRACT FROM AUTHOR]

Background: The main manifestation of Alzheimer's disease (AD) in patients and animal models is impaired memory function, characterized by amyloid-beta (Aβ) deposition and impairment of gamma oscillations that play an important role in perception and cognitive function. The therapeutic effect of gamma band stimulation in AD mouse models has been reported recently. Transcranial alternating current stimulation (tACS) is an emerging non-invasive intervention method, but at present, researchers have not completely understood the intervention effect of tACS. Thus, the intervention mechanism of tACS has not been fully elucidated, and the course of treatment in clinical selection also lacks theoretical support. Based on this issue, we investigated the effect of gamma frequency (40 Hz) tACS at different durations in a mouse model of AD. Materials and methods: We placed stimulating electrodes on the skull surface of APP/PS1 and wild-type control mice (n = 30 and n = 5, respectively). Among them, 20 APP/PS1 mice were divided into 4 groups to receive 20 min 40 Hz tACS every day for 1-4 weeks. The other 10 APP/PS1 mice were equally divided into two groups to receive sham treatment and no treatment. No intervention was performed in the wild-type control mice. The short-term memory function of the mice was examined by the Y maze. Aβ levels and microglia in the hippocampus were measured by immunofluorescence. Spontaneous electroencephalogram gamma power was calculated by the average period method, and brain connectivity was examined by cross-frequency coupling. Results: We found that the long-term treatment groups (21 and 28 days) had decreased hippocampal Aβ levels, increased electroencephalogram spontaneous gamma power, and ultimately improved short-term memory function. The treatment effect of the short-term treatment group (7 days) was not significant. Moreover, the treatment effect of the 14-day treatment group was weaker than that of the 21-day treatment group. Conclusion: These results suggest that long-term gamma-frequency tACS is more effective in treating AD by reducing Aβ load and improving gamma oscillation than short-term gamma-frequency tACS. [ABSTRACT FROM AUTHOR]

The hippocampus, a critical brain structure for spatial learning and memory, is susceptible to neurodegenerative disorders such as Alzheimer's disease (AD). The APPswe/PSEN1dE9 (APP/PS1) transgenic mouse model is widely used to study the pathology of AD. Although previous research has established AD-associated impairments in hippocampal-dependent learning and memory, the neurophysiological mechanisms underlying these cognitive dysfunctions remain less understood. To address this gap, we investigated the activities of place cells in both CA1 and CA3 hippocampal subregions, which have distinct yet complementary computational roles. Behaviorally, APP/PS1 mice demonstrated impaired spatial recognition memory compared to wild-type (WT) mice in the object location test. Physiologically, place cells in APP/PS1 mice showed deterioration in spatial representation compared to WT. Specifically, CA1 place cells exhibited significant reductions in coherence and spatial information, while CA3 place cells displayed a significant reduction in place field size. Both CA1 and CA3 place cells in APP/PS1 mice also showed significant disruptions in their ability to stably encode the same environment. Furthermore, the burst firing properties of these cells were altered to forms correlated with reduced cognition. Additionally, the theta rhythm was significantly attenuated in CA1 place cells of APP/PS1 mice compared to WT. Our results suggest that distinct alteration in the physiological properties of CA1 and CA3 place cells, coupled with disrupted hippocampal theta rhythm in CA1, may collectively contribute to impaired hippocampal-dependent spatial learning and memory in AD., Competing Interests: The authors declare no competing financial interests.

Background: In Alzheimer's disease (AD), synaptic dysfunction is thought to occur many years before the onset of cognitive decline.Objective: Detecting synaptic dysfunctions at the earliest stage of AD would be desirable in both clinic and research settings.Methods: Population voltage imaging allows monitoring of synaptic depolarizations, to which calcium imaging is relatively blind. We developed an AD mouse model (APPswe/PS1dE9 background) expressing a genetically-encoded voltage indicator (GEVI) in the neocortex. GEVI was restricted to the excitatory pyramidal neurons (unlike the voltage-sensitive dyes).Results: Expression of GEVI did not disrupt AD model formation of amyloid plaques. GEVI expression was stable in both AD model mice and Control (healthy) littermates (CTRL) over 247 days postnatal. Brain slices were stimulated in layer 2/3. From the evoked voltage waveforms, we extracted several parameters for comparison AD versus CTRL. Some parameters (e.g., temporal summation, refractoriness, and peak latency) were weak predictors, while other parameters (e.g., signal amplitude, attenuation with distance, and duration (half-width) of the evoked transients) were stronger predictors of the AD condition. Around postnatal age 150 days (P150) and especially at P200, synaptically-evoked voltage signals in brain slices were weaker in the AD groups versus the age- and sex-matched CTRL groups, suggesting an AD-mediated synaptic weakening that coincides with the accumulation of plaques. However, at the youngest ages examined, P40 and P80, the AD groups showed differentially stronger signals, suggesting "hyperexcitability" prior to the formation of plaques.Conclusion: Our results indicate bidirectional alterations in cortical physiology in AD model mice; occurring both prior (P40-80), and after (P150-200) the amyloid deposition. [ABSTRACT FROM AUTHOR]

Abstract Background Before the deposition of amyloid-beta plaques and the onset of learning memory deficits, patients with Alzheimer’s disease (AD) experience olfactory dysfunction, typified by a reduced ability to detect, discriminate, and identify odors. Rodent models of AD, such as the Tg2576 and APP/PS1 mice, also display impaired olfaction, accompanied by aberrant in vivo or in vitro gamma rhythms in the olfactory pathway. However, the mechanistic relationships between the electrophysiological, biochemical and behavioral phenomena remain unclear. Methods To address the above issues in AD models, we conducted in vivo measurement of local field potential (LFP) with a combination of in vitro electro-olfactogram (EOG), whole-cell patch and field recordings to evaluate oscillatory and synaptic function and pharmacological regulation in the olfactory pathway, particularly in the olfactory bulb (OB). Levels of protein involved in excitation and inhibition of the OB were investigated by western blotting and fluorescence staining, while behavioral studies assessed olfaction and memory function. Results LFP measurements demonstrated an increase in gamma oscillations in the OB accompanied by altered olfactory behavior in both APP/PS1 and 3xTg mice at 3–5 months old, i.e. an age before the onset of plaque formation. Fewer olfactory sensory neurons (OSNs) and a reduced EOG contributed to a decrease in the excitatory responses of M/T cells, suggesting a decreased ability of M/T cells to trigger interneuron GABA release indicated by altered paired-pulse ratio (PPR), a presynaptic parameter. Postsynaptically, there was a compensatory increase in levels of GABAAR α1 and β3 subunits and subsequent higher amplitude of inhibitory responses. Strikingly, the GABA uptake inhibitor tiagabine (TGB) ameliorated abnormal gamma oscillations and levels of GABAAR subunits, suggesting a potential therapeutic strategy for early AD symptoms. These findings reveal increased gamma oscillations in the OB as a core indicator prior to onset of AD and uncover mechanisms underlying aberrant gamma activity in the OB. Conclusions This study suggests that the concomitant dysfunction of both olfactory behavior and gamma oscillations have important implications for early AD diagnosis: in particular, awareness of aberrant GABAergic signaling mechanisms might both aid diagnosis and suggest therapeutic strategies for olfactory damage in AD.

Background: Obesity is a worldwide health problem that has been implicated in many diseases, including Alzheimer's disease (AD). AD is one of the most common neurodegenerative disorders and is characterized by two pathologies, including extracellular senior plaques composed of amyloid-β (Aβ) and intracellular neurofibrillary tangles (NFTs) consisting of abnormally hyperphosphorylated tau. According to current research, a high-fat diet (HFD) could exacerbate Aβ accumulation, oxidative damage, and cognitive defects in AD mice. However, the accurate role of HFD in the pathogenesis of AD is far more unclear.Objective: To explore the accurate role of HFD in the pathogenesis of AD.Methods: Open Field, Barns Maze, Elevated zero-maze, Contextual fear condition, Tail suspension test, western blotting, immunofluorescence, Fluoro-Jade C Labeling, Perls' Prussian blue staining, and ELISA were used.Results: HFD caused nonheme iron overload in the brains of APPswe/PS1dE9 (APP/PS1) mice. Furthermore, the administration of M30 (0.5 mg/kg) for iron chelation once every 2 days per os (p.o.) for 1 month remitted memory deficits caused by HFD in APP/PS1 mice. Notably, a variety of hematological parameters in whole blood had no difference after iron chelation. In addition, iron chelation effectively reduced synaptic impairment in hippocampus and neuronal degeneration in cortex in the HFD-fed APP/PS1 mice. Meanwhile, iron chelation decreased Aβ1-40 and Aβ1-42 level as well as neuroinflammation in HFD-fed APP/PS1 mice.Conclusion: These data enhance our understanding of how HFD aggravates AD pathology and cognitive impairments and might shed light on future preclinical studies. [ABSTRACT FROM AUTHOR]

THC has been used as a promising treatment approach for neurological disorders, but the highly psychoactive effects have largely warned off many scientists from pursuing it further. We conducted an intranasal treatment using low-dose THC on 12-month-old APP/PS1 mice daily for 3 months to overcome any potential psychoactive response induced by the systemic delivery. Our results demonstrate that the THC nasal treatment at 0.002 and 0.02 mg/kg significantly slowed the memory decline compared to that in the vehicle-treated transgenic mouse control group. An enzyme-linked immunosorbent assay showed that the Aβ1–40 and 1–42 peptides decreased in the THC-treated groups. The Western blot data indicate that long-term low-dose THC intranasal administration promoted p-tau level reduction and mitochondrial function marker redistribution. The blood biochemical parameter data demonstrate some insignificant changes in cytokine, immunoglobulin, and immune cell profiles during intranasal THC treatment. Intranasal delivery is a non-invasive and convenient method that rapidly targets therapeutics to the brain, minimizing systemic exposure to avoid unwanted adverse effects. Our study provides new insights into the role of low-dose THC intranasal treatment as a pharmacological strategy to counteract alterations in Alzheimer's disease-related cognitive performance. [ABSTRACT FROM AUTHOR]

Background: A decline of brain serotonin (5-HT) is held responsible for the changes in mood that can be observed in Alzheimer's disease (AD). However, 5-HT'ergic signaling is also suggested to reduce the production of pathogenic amyloid-β (Aβ).Objective: To investigate the effect of targeted inactivation of tryptophan hydroxylase-2 (Tph2), which is essential for neuronal 5-HT synthesis, on amyloidosis in amyloid precursor protein (APP)swe/presenilin 1 (PS1) ΔE9 transgenic mice.Methods: Triple-transgenic (3xTg) APP/PS1 mice with partial (+/-) or complete Tph2 knockout (-/-) were allowed to survive until 6 months old with APP/PS1, Tph2-/-, and wildtype mice. Survival and weight were recorded. Levels of Aβ42/40/38, soluble APPα (sAβPPα) and sAβPPβ, and cytokines were analyzed by mesoscale, neurotransmitters by mass spectrometry, and gene expression by quantitative PCR. Tph2, microglia, and Aβ were visualized histologically.Results: Tph2 inactivation in APP/PS1 mice significantly reduced viability, without impacting soluble and insoluble Aβ42 and Aβ40 in neocortex and hippocampus, and with only mild changes of soluble Aβ42/Aβ40. However, sAβPPα and sAβPPβ in hippocampus and Aβ38 and Aβ40 in cerebrospinal fluid were reduced. 3xTg-/-mice were devoid of Tph2 immunopositive fibers and 5-HT. Cytokines were unaffected by genotype, as were neocortical TNF, HTR2a and HTR2b mRNA levels in Tph2-/- mice. Microglia clustered around Aβ plaques regardless of genotype.Conclusion: The results suggest that Tph2 inactivation influences AβPP processing, at least in the hippocampus, although levels of Aβ are unchanged. The reduced viability of 3xTg-/-mice could indicate that 5-HT protects against the seizures that can impact the viability of APP/PS1 mice. [ABSTRACT FROM AUTHOR]

Soluble amyloid precursor protein-alpha (sAPPα) is a regulator of neuronal and memory mechanisms, while also having neurogenic and neuroprotective effects in the brain. As adult hippocampal neurogenesis is impaired in Alzheimer's disease, we tested the hypothesis that sAPPα delivery would rescue adult hippocampal neurogenesis in an APP/PS1 mouse model of Alzheimer's disease. An adeno-associated virus-9 (AAV9) encoding murine sAPPα was injected into the hippocampus of 8-month-old wild-type and APP/PS1 mice, and later two different thymidine analogues (XdU) were systemically injected to label adult-born cells at different time points after viral transduction. The proliferation of adult-born cells, cell survival after eight weeks, and cell differentiation into either neurons or astrocytes was studied. Proliferation was impaired in APP/PS1 mice but was restored to wild-type levels by viral expression of sAPPα. In contrast, sAPPα overexpression failed to rescue the survival of XdU+-labelled cells that was impaired in APP/PS1 mice, although it did cause a significant increase in the area density of astrocytes in the granule cell layer across both genotypes. Finally, viral expression of sAPPα reduced amyloid-beta plaque load in APP/PS1 mice in the dentate gyrus and somatosensory cortex. These data add further evidence that increased levels of sAPPα could be therapeutic for the cognitive decline in AD, in part through restoration of the proliferation of neural progenitor cells in adults. [ABSTRACT FROM AUTHOR]

With the growing popularity of touchscreen cognitive testing in rodents, it is imperative to understand the fundamental effects exposure to this paradigm can have on the animals involved. In this study, we set out to assess hippocampal-dependant learning in the APP/PS1 mouse model of Alzheimer's disease (AD) on two highly translatable touchscreen tasks – the Paired Associate Learning (PAL) task and the Trial Unique Non-Matching to Location (TUNL) task. Both of these tests are based on human tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and are sensitive to deficits in both mild cognitive impairment (MCI) and AD. Mice were assessed for deficits in PAL at 9–12 months of age, then on TUNL at 8–11 and 13–16 months. No cognitive deficits were evident in APP/PS1 mice at any age, contrary to previous reports using maze-based learning and memory tasks. We hypothesized that daily and long-term touchscreen training may have inadvertently acted as a cognitive enhancer. When touchscreen-tested mice were assessed on the Morris water maze, they showed improved task acquisition compared to naïve APP/PS1 mice and wild-type (WT) littermate controls. In addition, we show that touchscreen-trained WT and APP/PS1 mice show increased cell proliferation and immature neuron numbers in the dentate gyrus compared to behaviorally naïve WT and APP/PS1 mice. This result indicates that the touchscreen testing paradigm could improve cognitive performance, and/or mask an impairment, in experimental mouse models. This touchscreen-induced cognitive enhancement may involve increased neurogenesis, and possibly other forms of cellular plasticity. This is the first study to show increased numbers of proliferating cells and immature neurons in the hippocampus following touchscreen testing, and that touchscreen training can improve cognitive performance in maze-based spatial navigation tasks. This potential for touchscreen testing to induce cognitive enhancement, or other phenotypic shifts, in preclinical models should be considered in study design. Furthermore, touchscreen-mediated cognitive enhancement could have therapeutic implications for cognitive disorders. [ABSTRACT FROM AUTHOR]

• Rewarded executive function was assessed in APP/PS1 mice using touchscreens • APP/PS1 mice showed a subtle extinction deficit at middle-age • Old APP/PS1 mice showed a profound behavioural flexibility deficit • Genotype did not affect retinal health as measured by OCT or ERG, but age did • This is the first study to show deficits in rewarded extinction or reversal tasks in the APP/PS1 mice Executive function deficits in Alzheimer's disease (AD) occur early in disease progression and may be predictive of cognitive decline. However, no preclinical studies have identified deficits in rewarded executive function in the commonly used APPSwe/PS1∆E9 (APP/PS1) mouse model. To address this, we assessed 12-26 month old APP/PS1 mice on rewarded reversal and/or extinction tasks. 16-month-old, but not 13- or 26-month-old, APP/PS1 mice showed an attenuated rate of extinction. Reversal deficits were seen in 22-month-old, but not 13-month-old APP/PS1 animals. We then confirmed that impairments in reversal were unrelated to previously reported visual impairments in both AD mouse models and humans. Age, but not genotype, had a significant effect on markers of retinal health, indicating the deficits seen in APP/PS1 mice were directly related to cognition. This is the first characterisation of rewarded executive function in APP/PS1 mice, and has great potential to facilitate translation from preclinical models to the clinic. [ABSTRACT FROM AUTHOR]

Abstract Background Early-life stress (ES) is an emerging risk factor for later life development of Alzheimer’s disease (AD). We have previously shown that ES modulates amyloid-beta pathology and the microglial response to it in the APPswe/PS1dE9 mouse model. Because astrocytes are key players in the pathogenesis of AD, we studied here if and how ES affects astrocytes in wildtype (WT) and APP/PS1 mice and how these relate to the previously reported amyloid pathology and microglial profile. Methods We induced ES by limiting nesting and bedding material from postnatal days (P) 2–9. We studied in WT mice (at P9, P30, and 6 months) and in APP/PS1 mice (at 4 and 10 months) (i) GFAP coverage, cell density, and complexity in hippocampus (HPC) and entorhinal cortex (EC); (ii) hippocampal gene expression of astrocyte markers; and (iii) the relationship between astrocyte, microglia, and amyloid markers. Results In WT mice, ES increased GFAP coverage in HPC subregions at P9 and decreased it at 10 months. APP/PS1 mice at 10 months exhibited both individual cell as well as clustered GFAP signals. APP/PS1 mice when compared to WT exhibited reduced total GFAP coverage in HPC, which is increased in the EC, while coverage of the clustered GFAP signal in the HPC was increased and accompanied by increased expression of several astrocytic genes. While measured astrocytic parameters in APP/PS1 mice appear not be further modulated by ES, analyzing these in the context of ES-induced alterations to amyloid pathology and microglial shows alterations at both 4 and 10 months of age. Conclusions Our data suggest that ES leads to alterations to the astrocytic response to amyloid-β pathology.

Alzheimer’s disease (AD) is characterized by synaptic failure and neuronal loss. Recently, we demonstrated that artemisinins restored the levels of key proteins of inhibitory GABAergic synapses in the hippocampus of APP/PS1 mice, a model of cerebral amyloidosis. In the present study, we analyzed the protein levels and subcellular localization of α2 and α3 subunits of GlyRs, indicated as the most abundant receptor subtypes in the mature hippocampus, in early and late stages of AD pathogenesis, and upon treatment with two different doses of artesunate (ARS). Immunofluorescence microscopy and Western blot analysis demonstrated that the protein levels of both α2 and α3 GlyRs are considerably reduced in the CA1 and the dentate gyrus of 12-month-old APP/PS1 mice when compared to WT mice. Notably, treatment with low-dose ARS affected GlyR expression in a subunit-specific way; the protein levels of α3 GlyR subunits were rescued to about WT levels, whereas that of α2 GlyRs were not affected significantly. Moreover, double labeling with a presynaptic marker indicated that the changes in GlyR α3 expression levels primarily involve extracellular GlyRs. Correspondingly, low concentrations of artesunate (≤1 µM) also increased the extrasynaptic GlyR cluster density in hAPPswe-transfected primary hippocampal neurons, whereas the number of GlyR clusters overlapping presynaptic VIAAT immunoreactivities remained unchanged. Thus, here we provide evidence that the protein levels and subcellular localization of α2 and α3 subunits of GlyRs show regional and temporal alterations in the hippocampus of APP/PS1 mice that can be modulated by the application of artesunate.

With the growing popularity of touchscreen cognitive testing in rodents, it is imperative to understand the fundamental effects exposure to this paradigm can have on the animals involved. In this study, we set out to assess hippocampal-dependant learning in the APP/PS1 mouse model of Alzheimer’s disease (AD) on two highly translatable touchscreen tasks – the Paired Associate Learning (PAL) task and the Trial Unique Non-Matching to Location (TUNL) task. Both of these tests are based on human tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and are sensitive to deficits in both mild cognitive impairment (MCI) and AD. Mice were assessed for deficits in PAL at 9–12 months of age, then on TUNL at 8–11 and 13–16 months. No cognitive deficits were evident in APP/PS1 mice at any age, contrary to previous reports using maze-based learning and memory tasks. We hypothesized that daily and long-term touchscreen training may have inadvertently acted as a cognitive enhancer. When touchscreen-tested mice were assessed on the Morris water maze, they showed improved task acquisition compared to naïve APP/PS1 mice and wild-type (WT) littermate controls. In addition, we show that touchscreen-trained WT and APP/PS1 mice show increased cell proliferation and immature neuron numbers in the dentate gyrus compared to behaviorally naïve WT and APP/PS1 mice. This result indicates that the touchscreen testing paradigm could improve cognitive performance, and/or mask an impairment, in experimental mouse models. This touchscreen-induced cognitive enhancement may involve increased neurogenesis, and possibly other forms of cellular plasticity. This is the first study to show increased numbers of proliferating cells and immature neurons in the hippocampus following touchscreen testing, and that touchscreen training can improve cognitive performance in maze-based spatial navigation tasks. This potential for touchscreen testing to induce cognitive enhancement, or other phenotypic shifts, in preclinical models should be considered in study design. Furthermore, touchscreen-mediated cognitive enhancement could have therapeutic implications for cognitive disorders.

Alzheimer’s disease (AD) is a central nervous system degenerative disease, with no effective treatment to date. Administration of immune checkpoint inhibitors significantly reduces neuronal damage and tau hyperphosphorylation in AD, but the specific mechanism is unclear. Here, we found that programmed cell death-receptor 1 (PD1) and its ligand PDL1 were induced by an intracerebroventricular injection of amyloid-β; they were significantly upregulated in the brains of APP/PS1, 5×FAD mice and in SH-SY5Y-APP cell line compared with control. The PD1 and PDL1 levels positively correlated with the glycogen synthase kinase 3 beta (GSK3β) activity in various AD mouse models, and the PDL1-GSK3β immune complex was found in the brain. The application of PD1-blocking antibody reduced tau hyperphosphorylation and GSK3β activity and prevented memory impairments. Mechanistically, we identified PD1 as a critical regulator of GSK3β activity. These results suggest that the immune regulation of the PD1/PDL1 axis is closely involved in AD.

Background: Microglial cell iron load and inflammatory activation are significant hallmarks of late-stage Alzheimer's disease (AD). In vitro , microglia preferentially upregulate the iron importer, divalent metal transporter 1 (DMT1, gene name Slc11a2 ) in response to inflammatory stimuli, and excess iron can augment cellular inflammation, suggesting a feed-forward loop between iron import mechanisms and inflammatory signaling. However, it is not understood whether microglial iron import mechanisms directly contribute to inflammatory signaling and chronic disease in vivo . These studies determined the effects of microglial-specific knockdown of Slc11a2 on AD-related cognitive decline and microglial transcriptional phenotype., Methods: In vitro experiments and RT-qPCR were used to assess a role for DMT1 in amyloid-β-associated inflammation. To determine the effects of microglial Slc11a2 knockdown on AD-related phenotypes in vivo , triple-transgenic Cx3cr1 Cre - ERT2 ; Slc11a2 flfl ; APP/PS1 + or - mice were generated and administered corn oil or tamoxifen to induce knockdown at 5-6 months of age. Both sexes underwent behavioral analyses to assess cognition and memory (12-15 months of age). Hippocampal CD11b + microglia were magnetically isolated from female mice (15-17 months) and bulk RNA-sequencing analysis was conducted., Results: DMT1 inhibition in vitro robustly decreased Aβ-induced inflammatory gene expression and cellular iron levels in conditions of excess iron. In vivo , Slc11a2 KD APP/PS1 female, but not male, mice displayed a significant worsening of memory function in Morris water maze and a fear conditioning assay, along with significant hyperactivity compared to control WT and APP/PS1 mice. Hippocampal microglia from Slc11a2 KD APP/PS1 females displayed significant increases in Enpp2 , Ttr , and the iron-export gene, Slc40a1 , compared to control APP/PS1 cells. Slc11a2 KD cells from APP/PS1 females also exhibited decreased expression of markers associated with disease-associated microglia (DAMs), such as Apoe , Ctsb, Csf1 , and Hif1α ., Conclusions: This work suggests a sex-specific role for microglial iron import gene Slc11a2 in propagating behavioral and cognitive phenotypes in the APP/PS1 model of AD. These data also highlight an association between loss of a DAM-like phenotype in microglia and cognitive deficits in Slc11a2 KD APP/PS1 female mice. Overall, this work illuminates an iron-related pathway in microglia that may serve a protective role during disease and offers insight into mechanisms behind disease-related sex differences., Competing Interests: Competing Interests The authors declare that they have no competing interests.

Background: In Alzheimer's disease (AD), an increase in inflammation is distinctive. Amyloid precursor protein plus presenilin-1 (APP/PS1 mice) is a model for this illness. Chemokines secreted by central nervous system (CNS) cells could play multiple important roles in AD. Data looking for the chemokines involved in inflammatory mechanisms are lacking. To understand the changes that occur in the inflammation process in AD, it is necessary to improve strategies to act on specific inflammatory targets.Objective: Chemokines and their receptors involved in phagocytosis, demyelination, chemotaxis, and coagulation were the objective of our study.Methods: Female APPswe/PS1 double-transgenic mice (B6C3-Tg) were used and cortex brain from 20-22-month-old mice obtained and used to quantify chemokines and chemokine receptors expression using RT-PCR technique.Results: Significant inflammatory changes were detected in APP/PS1 compared to wild type mice. CCR1, CCR3, CCR4, and CCR9 were elevated, and CCR2 were decreased compared with wild type mice. Their ligands CCL7, CCL11, CCL17, CCL22, CCL25, and CXCL4 showed an increase expression; however, changes were not observed in CCL2 in APP/PS1 compared to wild type mice.Conclusion: This change in expression could explain the differences between AD patients and elderly people without this illness. This would provide a new strategy for the treatment of AD, with the possibility to act in specific inflammatory targets. [ABSTRACT FROM AUTHOR]

Neuroinflammation contributes to Alzheimer's disease (AD) progression. Secondary inflammatory insults trigger delirium and can accelerate cognitive decline. Individual cellular contributors to this vulnerability require elucidation. Using APP/PS1 mice and AD brain, we studied secondary inflammatory insults to investigate hypersensitive responses in microglia, astrocytes, neurons, and human brain tissue. The NLRP3 inflammasome was assembled surrounding amyloid beta, and microglia were primed, facilitating exaggerated interleukin‐1β (IL‐1β) responses to subsequent LPS stimulation. Astrocytes were primed to produce exaggerated chemokine responses to intrahippocampal IL‐1β. Systemic LPS triggered microglial IL‐1β, astrocytic chemokines, IL‐6, and acute cognitive dysfunction, whereas IL‐1β disrupted hippocampal gamma rhythm, all selectively in APP/PS1 mice. Brains from AD patients with infection showed elevated IL‐1β and IL‐6 levels. Therefore, amyloid leaves the brain vulnerable to secondary inflammation at microglial, astrocytic, neuronal, and cognitive levels, and infection amplifies neuroinflammatory cytokine synthesis in humans. Exacerbation of neuroinflammation to produce deleterious outcomes like delirium and accelerated disease progression merits careful investigation in humans. [ABSTRACT FROM AUTHOR]