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Telomere attrition is one of biological aging hallmarks and may be intervened to target multiple aging‐related diseases, including Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD). The objective of this study was to assess associations of leukocyte telomere length (TL) with AD/ADRD and early markers of AD/ADRD, including cognitive performance and brain magnetic resonance imaging (MRI) phenotypes. Data from European‐ancestry participants in the UK Biobank (n = 435,046) were used to evaluate whether mid‐life leukocyte TL is associated with incident AD/ADRD over a mean follow‐up of 12.2 years. In a subsample without AD/ADRD and with brain imaging data (n = 43,390), we associated TL with brain MRI phenotypes related to AD or vascular dementia pathology. Longer TL was associated with a lower risk of incident AD/ADRD (adjusted Hazard Ratio [aHR] per SD = 0.93, 95% CI 0.90–0.96, p = 3.37 × 10−7). Longer TL also was associated with better cognitive performance in specific cognitive domains, larger hippocampus volume, lower total volume of white matter hyperintensities, and higher fractional anisotropy and lower mean diffusivity in the fornix. In conclusion, longer TL is inversely associated with AD/ADRD, cognitive impairment, and brain structural lesions toward the development of AD/ADRD. However, the relationships between genetically determined TL and the outcomes above were not statistically significant based on the results from Mendelian randomization analysis results. Our findings add to the literature of prioritizing risk for AD/ADRD. The causality needs to be ascertained in mechanistic studies. [ABSTRACT FROM AUTHOR]

The pathogenesis of Alzheimer's disease (AD) is complicated and involves multiple contributing factors. Mounting evidence supports the concept that AD is an age-related metabolic neurodegenerative disease mediated in part by brain insulin resistance, and sharing similar metabolic dysfunctions and brain pathological characteristics that occur in type 2 diabetes mellitus (T2DM) and other insulin resistance disorders. Brain insulin signal pathway is a major regulator of branched-chain amino acid (BCAA) metabolism. In the past several years, impaired BCAA metabolism has been described in several insulin resistant states such as obesity, T2DM and cardiovascular disease. Disrupted BCAA metabolism leading to elevation in circulating BCAAs and related metabolites is an early metabolic phenotype of insulin resistance and correlated with future onset of T2DM. Brain is a major site for BCAA metabolism. BCAAs play pivotal roles in normal brain function, especially in signal transduction, nitrogen homeostasis, and neurotransmitter cycling. Evidence from animal models and patients support the involvement of BCAA dysmetabolism in neurodegenerative diseases including Huntington's disease, Parkinson's disease, and maple syrup urine disease. More recently, growing studies have revealed altered BCAA metabolism in AD, but the relationship between them is poorly understood. This review is focused on the recent findings regarding BCAA metabolism and its role in AD. Moreover, we will explore how impaired BCAA metabolism influences brain function and participates in the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

Background: Sleep characteristics associated with dementia are poorly defined and whether their associations vary by demographics and APOE genotype among older adults are unclear.Methods: This population-based cross-sectional study included 4742 participants (age ≥ 65 years, 57.1% women) living in rural China. Sleep parameters were measured using the self-rated questionnaires of the Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale. Global cognitive function was assessed with the Mini-Mental State Examination (MMSE). Dementia was diagnosed following the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria, and the National Institute on Aging-Alzheimer's Association criteria for Alzheimer's disease (AD). Data were analysed using multiple logistic and general linear regression models.Results: Dementia was diagnosed in 173 participants (115 with AD). Multivariable-adjusted odds ratio (OR) of dementia was 1.71 (95%CI, 1.07-2.72) for sleep duration ≤4 h/night (vs. > 6-8 h/night), 0.76 (0.49-1.18) for > 4-6 h/night, 1.63 (1.05-2.55) for > 8 h/night, 1.11 (1.03-1.20) for lower sleep efficiency (per 10% decrease), and 1.85 (1.19-2.89) for excessive daytime sleepiness. Very short sleep duration (≤4 h/night), lower sleep efficiency, and excessive daytime sleepiness were significantly associated with being diagnosed with AD (multivariable-adjusted OR range = 1.12-2.07; p < 0.05). The associations of sleep problems with dementia and AD were evident mainly among young-old adults (65-74 years) or APOE ε4 carriers. Among dementia-free participants, these sleep characteristics were significantly associated with a lower MMSE score.Conclusions: Self-reported sleep problems in dementia are characterized by very short or long sleep duration, low sleep efficiency, and excessive daytime sleepiness, especially among young-old people and APOE ε4 carriers.Trial Registration: ChiCTR1800017758 (Aug 13, 2018). [ABSTRACT FROM AUTHOR]

The durative endoplasmic reticulum stress (ERS) and subsequent apoptosis contributes to the development and progression of Alzheimer's disease (AD). MiR-326 can reduce pyruvate kinase M2 (PKM2) expression, leading to ERS. Whereas, lncRNA RPPH1 is able to increase dendritic spine density and protect hippocampal pyramidal neurons through targeting miR-326. Our study aims to investigate the regulation of lncRNA RPPH1 and miR-326/PKM2 on ERS and related apoptosis in AD. SH-SY5Y cells treated with Aβ25-35 were selected as an in vitro AD model. RPPH1 and miR-326 overexpression and silencing cells were established by transforming vectors. The expression of RPPH1 and miR-326 were detected by qRT-PCR. MTT, flow cytometric, intracellular calcium assay and Western blot were used to test the functions of RPPH1 and miR-326 in SH-SY5Y cell proliferation, apoptosis and ERS. Dual-luciferase assay was used to detect the interaction among RPPH1, miR-326 and PKM2. RPPH1 overexpression enhanced the viability of SH-SY5Y cells, and attenuated the apoptosis of of SH-SY5Y cells. Moreover, RPPH1 overexpression down-regulated ER stress related proteins such as GRP78, CHOP and cleaved caspase-12. Mechanistically, RPPH1 directly targeted miR-326, thereby counteracting its inhibitory effect on PKM2 expression, contributing to attenuation of apoptosis and ERS induced by Aβ25-35. Aβ25-35-induced ERS and apoptosis in SH-SY5Y cells can be attenuated by lncRNA RPPH1 through regulating miR-326/PKM2 axis. This study provided therapeutic options for AD patients. [ABSTRACT FROM AUTHOR]

Drug compounds including memantine moieties are an important group of biologically active agents for different pathologies, including the Alzheimer's disease. In the present study, a series of memantine derivatives incorporating amino acid residues have been synthesized and their neuroprotective in vitro evaluation in respect of the Alzheimer's disease, involving the effects on the resistance to Aβ toxicity, excitotoxicity, oxidative stress, hypoxia, and neuroinflammation has been studied. The cytotoxicities of the compounds were detected by CPE assay. TC50 and IC50 were determined using Reed and Muench method. Solubility and distribution were measured using a shake-flask method. Permeability of the compounds was studied using Franz diffusion cell and Permeapad™ barrier. These compounds displayed apparent multi-neuroprotective effects against copper-triggered Aβ toxicity, glutamate-induced excitotoxicity, and oxidative and hypoxic injuries. They also showed the ability to inhibit the inflammatory cytokine release from the activated microglia and potential anti-neuroinflammatory effects. Especially, two most promising compounds H-4-F-Phe-memantine and H-Tyr-memantine demonstrated the equivalent functional bioactivities in comparison with the positive control memantine hydrochloride. Higher solubility in muriatic buffer than in phosphate buffer was detected. The distribution coefficients showed the optimal lipophilicity for compounds. The presented results propose new class of memantine derivatives as potential drug compounds. Based on the experimental results, the correlations have been obtained between the biological, physicochemical parameters and structural descriptors. The correlation equations have been proposed to predict the properties of new memantine derivatives knowing only the structural formula. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), an aging-related neurodegenerative disease, is a major cause of dementia in the elderly. Although the early-onset (familial) AD is attributed to mutations in the genes coding for amyloid-β protein precursor (AβPP) and presenilin1/presenilin 2 (PS1/PS2), the cause for the late-onset AD (LOAD), which accounts for more than 95% of AD cases, remains unclear. Aging is the greatest risk factor for LOAD, whereas the apolipo protein E4 allele (APOEɛ4) is believed to be a major genetic risk factor in acquiring LOAD, with female APOEɛ4 carriers at highest risk. Nonetheless, not all the elderly, even older female APOEɛ4 carriers, develop LOAD, suggesting that other factors, including environmental exposure, must play a role. This review summarizes recent studies that show a potential role of environmental exposure, especially ozone and particulate matter exposure, in the development of AD. Interactions between environmental exposure, genetic risk factor (APOEɛ4), and sex in AD pathophysiology are also discussed briefly. Identification of environmental risk factor(s) and elucidation of the complex interactions between genetic and environmental risk factors plus aging and female sex in the onset of AD will be a key to our understanding of the etiology and pathogenesis of AD and the development of the strategies for its prevention and treatment. [ABSTRACT FROM AUTHOR]

Background: Few community-based studies have examined occurrence and progression of subjective cognitive decline (SCD). Objective: To investigate prevalence and progression of SCD among rural-dwelling Chinese elderly people. Methods: This cohort study included 2,488 cognitively unimpaired adults (age≥65 years) who were examined at baseline (2014-2015) and followed in 2018. Demographic, epidemiological, clinical, and neuropsychological data were collected via in-person interviews and clinical examinations following a structured questionnaire. At baseline, SCD was assessed using the self-rated Ascertain Dementia 8-item Questionnaire. At follow-up, Alzheimer's disease (AD) and vascular dementia (VaD) were clinically diagnosed following the international criteria. Data were analyzed using logistic regression models. Results: The prevalence of SCD was 40.07%. SCD at baseline was associated with the multivariable-adjusted odds ratio (OR) of 1.51 (95% confidence interval 1.10–2.07) for incident cognitive impairment, no dementia (CIND) and 3.11 (1.64–5.93) for incident AD. Among people with SCD at baseline, the multivariable-adjusted OR of incident CIND was 0.55(0.32–0.96) for hyperlipidemia; the multivariable-adjusted OR of incident AD was 1.21 (1.14–1.30) for older age, 0.32 (0.12–0.88) for high education, 2.60 (1.11–6.08) for carrying APOEɛ4 allele, and 0.34 (0.13–0.86) for high social support, whereas the multivariable-adjusted OR of incident VaD was 6.30 (1.71–23.18) for obesity. Conclusion: SCD affects over 40% of rural-dwelling cognitively unimpaired older adults in China. SCD is associated with accelerated progression to CIND and AD. Older age, lack of school education, APOEɛ4 allele, and low social support are associated with an increased risk of progression from SCD to AD, whereas obesity is related to accelerated progression to VaD. [ABSTRACT FROM AUTHOR]

Aging is the greatest risk factor for late-onset Alzheimer's disease (LOAD), which accounts for >95% of Alzheimer's disease (AD) cases. The mechanism underlying the aging-related susceptibility to LOAD is unknown. Cellular senescence, a state of permanent cell growth arrest, is believed to contribute importantly to aging and aging-related diseases, including AD. Senescent astrocytes, microglia, endothelial cells, and neurons have been detected in the brain of AD patients and AD animal models. Removing senescent cells genetically or pharmacologically ameliorates β-amyloid (Aβ) peptide and tau-protein-induced neuropathologies, and improves memory in AD model mice, suggesting a pivotal role of cellular senescence in AD pathophysiology. Nonetheless, although accumulated evidence supports the role of cellular senescence in aging and AD, the mechanisms that promote cell senescence and how senescent cells contribute to AD neuropathophysiology remain largely unknown. This review summarizes recent advances in this field. We believe that the removal of senescent cells represents a promising approach toward the effective treatment of aging-related diseases, such as AD. [ABSTRACT FROM AUTHOR]

Abstract: Amyloid-β (Aβ) peptides accumulate in the brain and initiate a cascade of pathologic events in Alzheimer's disease. The receptor for advanced glycation end products (RAGE) has been implicated to mediate Aβ-induced perturbations in the neurovascular unit (NVU). We demonstrated that pinocembrin exhibits neuroprotection through inhibition of the Aβ and/or RAGE pathway, but the therapeutic role and mechanism involved are not ascertained. Here, we report that a 3-month treatment with pinocembrin prevents the cognition decline in APP/PS1 transgenic mice without altering Aβ burden and oxidative stress. Instead, pinocembrin is effective in conferring neurovascular protection through maintenance of neuropil ultrastructure, reduction of glial activation and levels of inflammatory mediators, preservation of microvascular function, improving the cholinergic system by conserving the ERK-CREB-BDNF pathway, and modulation of RAGE-mediated transduction. Furthermore, in an in vitro model, pinocembrin provides the NVU protection against fibrillar Aβ1–42, accompanied by regulation of neurovascular RAGE pathways. Our findings indicate that pinocembrin improves cognition, at least in part, attributable to the NVU protection, and highlights pinocembrin as a potential therapeutic strategy for the prevention and/or treatment of Alzheimer's disease. [Copyright &y& Elsevier]

Abstract: Quercetin has demonstrated protective effects against Aβ-induced toxicity on both neurons and endothelial cells. However, whether or not quercetin has an effect on the neurovascular coupling is unclear. In the present study, we aim to investigate the anti-amnesic effects of quercetin and to explore the underlying mechanisms. Aβ25–35 (10 nmol) was administrated to mice i.c.v. Quercetin was administrated orally for 8 days after injection. Learning and memory behaviors were evaluated by measuring spontaneous alternation in Morris Water Maze test and the step-through positive avoidance test. The regional cerebral blood flow was monitored before the Aβ25–35 injection and on seven consecutive days after injection. Mice were sacrificed and cerebral cortices were isolated on the last day. The effects of quercetin on the neurovascular unit (NVU) integrity, microvascular function and cholinergic neuronal changes, and the modification of signaling pathways were tested. Our results demonstrate that quercetin treatment for Aβ25–35-induced amnesic mice improved the learning and memory capabilities and conferred robust neurovascular coupling protection, involving maintenance of the NVU integrity, reduction of neurovascular oxidation, modulation of microvascular function, improvement of cholinergic system, and regulation of neurovascular RAGE signaling pathway and ERK/CREB/BDNF pathway. In conclusion, in Aβ25–35-induced amnesic mice, optimal doses of quercetin administration were beneficial. Quercetin protected the NVU likely through reduction of oxidative damage, inactivation of RAGE-mediated pathway and preservation of cholinergic neurons, offering an alternative medication for Alzheimer''s disease. [Copyright &y& Elsevier]

Abstract: The present paper is to examine whether liquiritigenin is able to attenuate the Alzheimer''s-like learning and memory deficits in a transgenic (Tg) mouse model that over-expresses amyloid protein precursor (APP), and explores the underlying mechanisms. Consistent with our previous observations, we found that treatment with liquiritigenin improved the behavioral performance of Tg mice and it attenuated the protein expression of oligomeric form of amyloid β-peptide (Aβ). Furthermore, treatment with liquiritigenin inhibited astrocytosis in the hippocampus, and it may through its inhibitory activities on Notch-2, an important molecular regulating neural proliferation and differentiation. These findings provide evidence for beneficial activity of liquiritigenin in a mouse model of Alzheimer''s disease and support the continued investigation of Notch signaling pathway as a target for treatment of Alzheimer''s disease. [Copyright &y& Elsevier]

Abstract: Alzheimer''s disease involves the complex and interconnected cascade of cellular and molecular events. Only a few treatments are available to slow the course of the disease at present. Recent studies suggest that neurovascular unit serves to maintain cerebral homeostasis, and pathological interactions between components of neurovascular unit lead to cerebral dysfunction. In present study, we established a functional unit trying to target major components of the neurovascular unit by the co-culture of rat cortical parenchymal culture and cerebral microvascular endothelial cells. This entity allowed the application of techniques such as immunofluorescent imaging and biological assays under defined conditions. The morphology of cell types, blood–brain barrier function and neuronal activation were investigated. The insight revealed that targeting components of the neurovascular unit, rather than just the neuron, might be a priority in Alzheimer''s disease and more likely to provide cerebroprotection. [Copyright &y& Elsevier]

Background: Neuroinflammation has been known to play a critical role in the pathogenesis of Alzheimer's disease (AD). Activation of microglia and astrocytes is a characteristic of brain inflammation. Epidemiological studies have shown that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) delays the onset of AD and suppresses its progression. Methyl salicylate-2-O-β-D-lactoside (DL0309) is a new molecule chemically related to salicylic acid. The present study aimed to evaluate the anti-inflammatory effects of DL0309.Findings: Our studies show that DL0309 significantly inhibits lipopolysaccharide (LPS)-induced release of the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α; and the expression of the inflammation-related proteins iNOS, COX-1, and COX-2 by microglia and astrocytes. At a concentration of 10 μM, DL0309 prominently inhibited LPS-induced activation of NF-κB in glial cells by blocking phosphorylation of IKK and p65, and by blocking IκB degradation.Conclusions: We demonstrate here for the first time that DL0309 exerts anti-inflammatory effects in glial cells by suppressing different pro-inflammatory cytokines and iNOS/NO. Furthermore, it also regulates the NF-κB signaling pathway by blocking IKK and p65 activation and IκB degradation. DL0309 also acts as a non-selective COX inhibitor in glial cells. These studies suggest that DL0309 may be effective in the treatment of neuroinflammatory disorders, including AD. [ABSTRACT FROM AUTHOR]

• miR-25802 upregulation is involved in the pathological progression of AD. • miR-25802 regulates microglia-mediated neuroinflammation in AD. • miR-25802 targets KLF4 to regulate NF-κB signaling. • The miR-25802/KLF4/NF-κB axis has a regulatory role in cognitive deficits in AD. Microglia-mediated neuroinflammation plays a critical role in the occurrence and progression of Alzheimer's disease (AD). In recent years, studies have increasingly explored microRNAs as biomarkers and treatment interventions for AD. This study identified a novel microRNA termed miR-25802 from our high-throughput sequencing dataset of an AD model and explored its role and the underlying mechanism. The results confirmed the miRNA properties of miR-25802 based on bioinformatics and experimental verification. Expression of miR-25802 was increased in the plasma of AD patients and in the hippocampus of APP/PS1 and 5 × FAD mice carrying two and five familial AD gene mutations. Functional studies suggested that overexpression or inhibition of miR-25802 respectively aggravated or ameliorated AD-related pathology, including cognitive disability, Aβ deposition, microglial pro-inflammatory phenotype activation, and neuroinflammation, in 5 × FAD mice and homeostatic or LPS/IFN-γ-stimulated EOC20 microglia. Mechanistically, miR-25802 negatively regulates KLF4 by directly binding to KLF4 mRNA, thus stimulating microglia polarization toward the pro-inflammatory M1 phenotype by promoting the NF-κB-mediated inflammatory response. The results also showed that inhibition of miR-25802 increased microglial anti-inflammatory M2 phenotype activity and suppressed NF-κB-mediated inflammatory reactions in the brains of 5 × FAD mice, while overexpression of miR-25802 exacerbated microglial pro-inflammatory M1 activity by enhancing NF-κB pathways. Of note, AD-associated manifestations induced by inhibition or overexpression of miR-25802 via the NF-κB signaling pathway were reversed by KLF4 silencing or upregulation. Collectively, these results provide the first evidence that miR-25802 is a regulator of microglial activity and establish the role of miR-25802/KLF4/NF-κB signaling in microglia-mediated neuroinflammation, suggesting potential therapeutic targets for AD. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel nanopeptide is self-assembled from maize tetrapeptide anchored AuNPs. • Nanopeptide has a neuroprotective effect on l -glutamate-induced extracellular model. • Nanopeptides have therapeutic effects on murine Alzheimer's disease models. • Nanopeptides may reduce model injury through the Nrf2/Keap1 signaling pathway. Nanopeptide assembled from peptide-anchored nanoparticles possess an enormous research potential in the field of cellular medicine and disease treatment. The aim of this study was to explore the neuroprotective effects of maize tetrapeptide anchored gold nanoparticles against l -glutamic acid-induced PC12 cell apoptosis and a murine Alzheimer's disease model induced by aluminum chloride and d -galactose. The results revealed that the nanopeptide antioxidant inhibited intracellular ROS accumulation and promoted cell differentiation than that of maize bioactive tetrapeptide. Compared with untreated Alzheimer's disease model mice, nanopeptide administration shortened the escape latency time in a water maze test and improved the movements in the autonomic activity test. After 16 days of nanopeptide administration, the central cholinergic system function of acetylcholine and cholineacetyltransferase were enhanced, and the level of acetylcholinesterase was reduced. It also increased superoxide dismutase and glutathione peroxidase activity in sera and hypothalami. Moreover, nanopeptide treatment upregulated cerebral nuclear factor erythroid 2-related factor 2 and heme-oxygenase-1 and downregulated kelch-like ECH-associated protein 1 relative to untreated Alzheimer's disease model mice. Thus, the novel nanopeptide is expected to be used as the neuroprotective agent to prevent Alzheimer's disease. [ABSTRACT FROM AUTHOR]

It is widely accepted that β-amyloid oligomers (Aβos) play a key role in the progression of Alzheimer's disease (AD) by inducing neuron damage and cognitive impairment, but Aβos are highly heterogeneous in their size, structure and cytotoxicity, making the corresponding studies tough to carry out. Nevertheless, a number of studies have recently made remarkable progress in the describing the characteristics and pathogenicity of Aβos. We here review the mechanisms by which Aβos exert their neuropathogenesis for AD progression, including receptor binding, cell membrane destruction, mitochondrial damage, Ca2+ homeostasis dysregulation and tau pathological induction. We also summarize the characteristics and pathogenicity such as the size, morphology and cytotoxicity of dimers, trimers, Aβ*56 and spherical oligomers, and suggest that Aβos may play a different role at different phases of AD pathogenesis, resulting in differential consequences on neuronal synaptotoxicity and survival. It is warranted to investigate the temporal sequence of Aβos in AD human brain and examine the relationship between different Aβos and cognitive impairment. [ABSTRACT FROM AUTHOR]

High sucrose can induce tau hyperphosphorylation and cognitive dysfunction/memory impairment as observed in Alzheimer's disease (AD). Rutaecarpine, a specific (transient receptor potential vanilloid 1 [TRPV1]) agonist, is neuroprotective against high sucrose diet-induced impairment, but detailed mechanisms are still elusive. In this study, we investigated whether rutaecarpine mitigates high sucrose diet-induced pathological alterations and cognitive in AD-like mice. Mice were administered fodder containing 0.01% rutaecarpine and 20% sucrose solution. Our results showed that rutaecarpine significantly attenuated high sucrose diet-induced spatial memory impairment and enhanced synaptic plasticity; rutaecarpine prevented high sucrose diet-induced tau hyperphosphorylation by decreasing glycogen synthase kinase-3β (GSK-3β) activity; activation of GSK-3β reversed the protective effect of rutaecarpine on learning and memory deficits, synaptic plasticity, and tau hyperphosphorylation induced by high-glucose diet significantly, suggesting that GSK-3β activation is required for high glucose-induced tau hyperphosphorylation. These results demonstrated that rutaecarpine can mitigate high sucrose diet-induced hyperphosphorylation of AD-associated tau protein and cognitive impairment by inhibiting GSK-3β, which supported that dietary rutaecarpine might have a promising use for therapeutic intervention of AD. [ABSTRACT FROM AUTHOR]

Background: Sedentary behavior is associated with cognitive impairment, but the neuropathological mechanisms underlying their associations are poorly understood. Objective: To investigate the associations of accelerometer-measured sedentary behavior patterns with brain structure and cognition, and further to explore the potential mechanisms. Methods: This community-based study included 2,019 older adults (age≥60 years, 59% women) without dementia derived from participants in the baseline examination of MIND-China (2018–2020). We assessed sedentary parameters using an accelerometer and cognitive function using a neuropsychological test battery. Structural brain markers were assessed on the structural brain MRI scans in a subsample (n = 1,009). Data were analyzed using the general linear, isotemporal substitution, and mediation models. Results: In the total sample (n = 2,019), adjusting for multiple covariates and moderate-to-vigorous-intensity physical activity, longer mean sedentary bout duration was linearly related with lower z-scores of global cognition, verbal fluency, and memory (ptrend < 0.05), whereas greater total sedentary time was linearly associated with lower z-scores of global cognition, verbal fluency, and memory only among individuals with long sedentary time (>10 h/day) (ptrend < 0.05); Breaking up sedentary time with same amount of light-intensity physical activity was significantly associated with higher verbal fluency and memory z-scores (p < 0.05). In the MRI subsample (n = 1,009), separately entering structural brain MRI markers into the mediation models substantially attenuated the associations of mean sedentary bout duration with global cognition, verbal fluency, and memory z-scores. Conclusion: Prolonged uninterrupted sedentary time is associated with poor global cognition, memory, and verbal fluency among rural older adults, and structural brain markers could partially mediate the association. [ABSTRACT FROM AUTHOR]

Background: Plasma biomarkers have emerged as a promising approach for characterizing pathophysiology in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Objective: We aimed to characterize plasma biomarkers for AD and neurodegeneration across the AD clinical continuum, and to assess their ability to differentiate between AD, MCI, and normal cognition. Methods: This population-based study engaged 1,446 rural-dwelling older adults (age ≥60 years, 61.0% women) derived from MIND-China; of these, 402 were defined with MCI and 142 with AD. Plasma amyloid-β (Aβ), total tau (t-tau), and neurofilament light chain (NfL) concentrations were analyzed using the Simoa platform. Data were analyzed using linear and logistic regression models, and receiver operating characteristic (ROC) analysis. Results: Across the AD clinical spectrum, plasma Aβ40 and NfL increased, whereas Aβ42/Aβ40 ratio decreased. Plasma t-tau was higher in people with AD dementia than those with MCI or normal cognition. Plasma NfL outperformed other biomarkers in differentiating AD from normal cognition (area under the ROC curve [AUC] = 0.75), but all plasma biomarkers performed poorly to distinguish MCI from normal cognition (AUC <0.60). Plasma NfL in combination with age, sex, education, and APOE genotype yielded the AUC of 0.87 for differentiating between AD and normal cognition, 0.79 between AD and MCI, and 0.64 between MCI and normal cognition. Conclusions: In this Chinese population, AD plasma biomarkers vary by age, sex, and APOE genotype. Plasma Aβ, t-tau, and NfL differ across the AD clinical spectrum, and plasma NfL appears to be superior to plasma Aβ and t-tau for defining the clinical spectrum. [ABSTRACT FROM AUTHOR]

The cause for the late-onset (sporadic) Alzheimer’s disease (AD), which accounts for 95% of AD cases, is unknown and most likely conferred by complex interactions between genetic and environmental risk factors plus aging. How the genetic and environmental risk factors as well as aging interact, leading to AD, however, is unknown. In this study, we explored the potential interactions between ApoE4, a genetic risk factor, O 3 , an environmental risk factor, and aging in the induction of memory impairment, using human ApoE4 and ApoE3 (the majority of human population carry the ApoE3 gene) targeted replacement (TR) male mice. The results show that exposure to O 3 following a cyclic exposure protocol, which mimics human exposure scenarios, impairs memory of old ApoE3 TR mice, although it has no significant effect on the memory of young ApoE3 and ApoE4 or old ApoE4 TR mice. The concentrations of glutathione (GSH), an important antioxidant, decrease with age and with O 3 exposure in frontal cortex (FC) and hippocampus, two brain areas affected mainly in AD, in ApoE3 TR mice, but only in FC of ApoE4 TR mice. The GSH and GSSG redox potentials decrease with age in the FC and hippocampus of ApoE3, but not ApoE4, TR mice; O 3 exposure, on the other hand, reduces the redox potential in young ApoE3 and old ApoE4 TR mice. Cysteine concentrations decrease with age and with O 3 exposure in both FC and hippocampus in ApoE3, but not in ApoE4, TR mice. The cysteine/cystine redox potentials, a major extracellular redox couple, decrease with O 3 exposure in both brain areas in young and old ApoE3 TR mice, but only in the frontal cortex of young ApoE4 TR mice. Together, the results suggest that male ApoE3 TR mice are more sensitive to aging- and O 3 -induced oxidative stress than ApoE4 TR mice, although young ApoE4 mice per se experience increased level of oxidative stress, compared to young ApoE3 TR mice. The results also suggest that increased sensitivity to oxidative stress may underlie memory loss in O 3 exposed old ApoE3 TR mice. As ApoE4 mainly affects females, interactions between ApoE4, O 3 , and aging in modulation of brain oxidative stress levels and memory in females warrant further investigation. [ABSTRACT FROM AUTHOR]

Background and Purpose: Immunotherapeutic intervention is one of the most promising strategies for the prevention and treatment of Alzheimer's disease (AD). Although they showed great success in AD mouse models, the clinical trials of many immune approaches failed due to low efficacy and safety. Thus, an animal model which can show the potential side effects of vaccines or antibodies is urgently needed. In this study, we generated EAE/AD mice by crossing APP/PS1 mice with experimental autoimmune encephalomyelitis (EAE) mice. We then investigated the efficacy and safety of two vaccines: the immunogens of which were Aβ1-42 aggregates (Aβ42 vaccine) and an oligomer-specific conformational epitope (AOE1 vaccine), respectively.Experimental Approach: EAE/AD mice were immunized with the Aβ42 vaccine or AOE1 vaccine five times at biweekly intervals. After the final immunization, cognitive function was evaluated by the Morris water maze, Y maze, and object recognition tests. Neuropathological changes in the mouse brains were analysed by immunohistochemistry and ELISA.Key Results: In contrast to previous findings in conventional AD animal models, Aβ42 immunization promoted neuroinflammation, enhanced Aβ levels and plaque burden, and failed to restore cognitive deficits in EAE/AD mice. By contrast, AOE1 immunization dramatically attenuated neuroinflammation, reduced Aβ levels, and improved cognitive performance in EAE/AD mice.Conclusion and Implications: These results suggest that the EAE/AD mouse model can exhibit the potential side effects of AD immune approaches that conventional AD animal models fail to display. Furthermore, strategies specifically targeting Aβ oligomers may be safe and show clinical benefit for AD treatment. [ABSTRACT FROM AUTHOR]

Background: Evidence has emerged that altered ventricular electrocardiogram profiles are associated with dementia, but the neuropathological mechanisms underlying their associations are poorly understood. Objective: To investigate the interrelationships of ventricular electrocardiogram profiles with dementia and plasma Alzheimer's disease (AD) biomarkers among older adults. Methods: This population-based cross-sectional study included 5,153 participants (age ≥65 years; 57.3% women) living in rural communities in China; of these, 1,281 had data on plasma amyloid-β (Aβ)40, Aβ42, total-tau, and neurofilament light chain (NfL) protein. The QT, QTc, JT, JTc, QRS intervals, and QRS axis were derived from the 10-second electrocardiogram recording. The DSM-IV criteria were followed for clinical diagnosis of dementia, the NIA-AA criteria for AD, and the NINDS-AIREN criteria for vascular dementia (VaD). Data were analyzed using general linear models, multinomial logistic models, and restricted cubic splines. Results: Of the 5,153 participants, 299 (5.8%) were diagnosed with dementia, including 194 with AD and 94 with VaD. Prolonged QT, QTc, JT, and JTc intervals were significantly associated with all-cause dementia, AD, and VaD (p < 0.05). Left QRS axis deviation was significantly associated with all-cause dementia and VaD (p < 0.01). In the subsample of plasma biomarkers (n = 1,281), prolonged QT, JT, and JTc intervals were significantly associated with a lower Aβ42/Aβ40 ratio and higher plasma NfL concentrations (p < 0.05). Conclusion: Alterations in ventricular repolarization and depolarization are independently associated with all-cause dementia, AD, VaD, and AD plasma biomarkers in older adults (age ≥65 years). Ventricular electrocardiogram parameters may be valuable clinical markers for dementia and the underlying AD pathologies and neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: Microvascular dysfunction (MVD) may contribute to cognitive impairment and Alzheimer's disease, but evidence is limited. Objective: To investigate the association of composite and organ-specific MVD burden with mild cognitive impairment (MCI) and cognition among rural-dwelling Chinese older adults. Methods: In this population-based cross-sectional study, we assessed MVD makers using optical coherence tomographic angiography for retinal microvasculature features, brain magnetic resonance imaging scans for cerebral small vessel disease (CSVD), and serum biomarkers for MVD. A composite MVD score was generated from the aforementioned organ-specific parameters. We used a neuropsychological test battery to assess memory, verbal fluency, attention, executive function, and global cognitive function. MCI, amnestic MCI (aMCI), and non-amnestic MCI (naMCI) were diagnosed following the Petersen's criteria. Data was analyzed with the linear and logistic regression models. Results: Of the 274 dementia-free participants (age≥65 years), 56 were diagnosed with MCI, including 47 with aMCI and 9 with naMCI. A composite MVD score was statistically significantly associated with an odds ratio (OR) of 2.70 (95% confidence interval 1.12–6.53) for MCI and β-coefficient of –0.29 (–0.48, –0.10) for global cognitive score after adjustment for socio-demographics, lifestyle factors, APOE genotype, the Geriatric Depression Scale score, serum inflammatory biomarkers, and cardiovascular comorbidity. A composite score of retinal microvascular morphology was associated with a multivariable-adjusted OR of 1.72 (1.09–2.73) for MCI and multivariable-adjusted β-coefficient of –0.11 (–0.22, –0.01) for global cognitive score. A composite CSVD score was associated with a lower global cognitive score (β= –0.10; –0.17, –0.02). Conclusion: Microvascular dysfunction, especially in the brain and retina, is associated with MCI and poor cognitive function among rural-dwelling older adults. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a major cause of dementia in the elderly with no effective treatment. Accumulation of amyloid-β peptide (Aβ) in the brain is a pathological hallmark of AD and is believed to be a central disease-causing and disease-promoting event. In a previous study, we showed that deletion of plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of tissue type and urokinase type plasminogen activators (tPA and uPA), significantly reduced brain Aβ load in APP/PS1 mice, an animal model of familial AD. In this study, we further show that oral administration of TM5275, a small molecule inhibitor of PAI-1, for a period of 6 weeks, inhibits the activity of PAI-1 and increases the activities of tPA and uPA as well as plasmin, which is associated with a reduction of Aβ load in the hippocampus and cortex and improvement of learning/memory function in APP/PS1 mice. Protein abundance of low density lipoprotein related protein-1 (LRP-1), a multi ligand endocytotic receptor involved in transporting Aβ out of the brain, as well as plasma Aβ42 are increased, whereas the expression and processing of full-length amyloid-β protein precursor is not affected by TM5275 treatment in APP/PS1 mice. In vitro studies further show that PAI-1 increases, whereas TM5275 reduces, Aβ40 level in the culture medium of SHSY5Y-APP neuroblastoma cells. Collectively, our data suggest that TM5275 improves memory function of APP/PS1 mice, probably by reducing brain Aβ accumulation through increasing plasmin-mediated degradation and LRP-1-mediated efflux of Aβ in the brain. [ABSTRACT FROM AUTHOR]

Oxidative stress is one of the potential causes of nervous system disease. Ginseng extract possesses excellent antioxidant activity; however, little research on the function of the ginseng fibrous root. This study aimed to investigate the neuroprotective effects of ginseng fibrous root to alleviate the pathogenesis of Alzheimer's disease (AD) against oxidative stress. Ginseng fibrous root enzymatic hydrolysate (GFREH) was first prepared by digesting ginseng fibrous roots with alkaline protease. In vitro, the GFREH showed antioxidant activities in free radical scavenging mechanisms. With a cellular model of AD, GFREH inhibited the increase in Ca2+ levels and intracellular ROS content, maintained the balance of mitochondrial membrane potential, and relieved L-glutamic acid-induced neurotoxicity. In vivo, GFREH improved the survival rate of Caenorhabditis elegans (C. elegans) under oxidative stress, upregulated SOD-3 expression, and reduced reactive oxygen species (ROS) content. Therefore, our findings provide evidence for the alleviation effect of GFREH against oxidative stress in neuroprotection, which may accelerate the development of anti-Alzheimer's drugs and treatments in the future. [ABSTRACT FROM AUTHOR]

Glutamate is an excitatory neurotransmitter in the nervous system. Excessive glutamate transmission can lead to increased calcium ion expression, related to increased neurotoxicity. Memantine is used for treating patients with Alzheimer's disease (AD) due to its protective action on the neurons against toxicity caused by over activation of N-methyl-D-aspartate receptors. Nootropics, also called "smart drugs", are used for the treatment of cognitive deficits. In this work, we evaluate the neuroprotective action of four memantine analogues of glycine derivatives, including glycyl-glycine, glycyl-glycyl-glycine, sarcosine, dimethylglycine and three conjugates with nootropics, modafinil, piracetam and picamilon. The new structural memantine derivatives improved cell viability against copper-induced neurotoxicity in APPswe cells and glutamate-induced neurotoxicity in SH-SY5Y cells. Among these novel compounds, modafinil-memantine, piracetam-memantine, sarcosine-memantine, dimethylglycine-memantine, and glycyl-glycine-memantine were demonstrated with good EC50 values of the protective effects on APPswe cells, accompanied with moderate amelioration from glutamate-induced neurotoxicity. In conclusion, our study demonstrated that novel structural derivatives of memantine might have the potential to develop promising lead compounds for the treatment of AD. The solubility of memantine analogues with nootropics and memantine analogues with glycine derivatives in buffer solutions at pH 2.0 and pH 7.4 simulating the biological media at 298.15 K was determined and the mutual influence of the structural fragments in the molecules on the solubility behavior was analyzed. The significative correlation equations relating the solubility and biological properties with the structural HYBOT (Hydrogen Bond Thermodynamics) descriptors were derived. These equations would greatly simplify the task of the directed design of the memantine analogues with improved solubility and enhanced bioavailability. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by cognitive dysfunction. The role of long non-coding RNAs (lncRNAs) with the action of competitive endogenous RNA (ceRNA) in AD remains unclear. The present study aimed to identify significantly differentially expressed lncRNAs (SDELs) and establish lncRNA-associated ceRNA networks via RNA sequencing analysis and a quantitative real-time Polymerase Chain Reaction (qPCR) assay using transgenic mice with five familial AD mutations. A total of 53 SDELs in the cortex and 51 SDELs in the hippocampus were identified, including seven core SDELs common to both regions. The functions and pathways were then investigated through the potential target genes of SDELs via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, which indicate biological effects, action distributions, and pathological transductions associated with AD. Based on the ceRNA hypothesis, integrated ceRNA networks in the cortex and hippocampus of lncRNA-miRNA-mRNA were constructed. The core SDEL-mediated ceRNA relationship was established and the expression of these RNAs was verified by qPCR. The results identified lncRNA ENSMUST00000127786 and highlighted miRNAs and mRNAs as potential key mediators in AD. These findings provide AD-derived lncRNA-mediated ceRNA profiles, and further experimental evidence is needed to confirm these identified ceRNA regulatory relationships. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disease with the hallmark of aggregation of beta-amyloid (Aβ) into extracellular fibrillar deposition. Accumulating evidence suggests that soluble toxic Aβ oligomers exert diverse roles in neuronal cell death, oxidative stress, neuroinflammation, and the eventual pathogenesis of AD. Aβ is derived from the sequential cleavage of amyloid-β precursor protein (APP) by β-secretase (BACE1) and γ-secretase. The current effect of single targeting is not ideal for the treatment of AD. Therefore, developing multipotent agents with multiple properties, including anti-Aβ generation and anti-Aβ aggregation, is attracting more attention for AD treatment. Previous studies indicated that Quercetin was able to attenuate the effects of several pathogenetic factors in AD. Here, we showed that naturally synthesized Quercetin-3-O-glc-1-3-rham-1-6-glucoside (YCC31) could inhibit Aβ production by reducing β-secretase activity. Further investigations indicated that YCC31 could suppress toxic Aβ oligomer formation by directly binding to Aβ. Moreover, YCC31 could attenuate Aβ-mediated neuronal death, ROS and NO production, and pro-inflammatory cytokines release. Taken together, YCC31 targeting multiple pathogenetic factors deserves further investigation for drug development of AD. [Display omitted] [ABSTRACT FROM AUTHOR]

• TOMM40 genotype but not PVRL2 gene was associated with Alzheimer's disease in Chinese older adults, depending on APOE genotype. • TOMM40 could interact with PVRL2 to substantially increase the likelihood of Alzheimer's disease. • The TOMM40 GG genotype was associated with low plasma Aβ42 concentration and the Aβ42-to-Aβ40 ratio. Genetic studies have identified Alzheimer's disease (AD)-associated SNPs in TOMM40 and PVRL2 genes, but the underlying mechanisms remain unknown. We examined their associations and interactions with AD risk and plasma biomarkers among Chinese older adults. This population-based study included 4876 participants. TOMM40 (rs2075650) and PVRL2 (rs6859) polymorphisms were detected using multiple-polymerase chain reaction amplification. Plasma Aβ40, Aβ42, and t-tau concentrations were measured using SIMOA in a subsample (n = 1257). AD was diagnosed following the international criteria. Data were analyzed using multiple logistic and general linear models. AD was diagnosed in 182 participants. The multiadjusted odds ratio of AD was 6.24 (95% CI 1.73–22.48) for TOMM40 GG, 1.47 (0.89–2.42) for PVRL2 AA, and 12.87 (3.97–41.73) for having both risk alleles (P interaction = 0.0003). Among APOE ε3/ε3 carriers, the multiadjusted odds ratio of AD associated with TOMM40 AG was 2.90(1.15–7.31). In biomarker subsample, TOMM40 GG was significantly associated with lower plasma Aβ42 and the Aβ42-to-Aβ40 ratio (p < 0.05). TOMM40 genotype is differentially associated with AD risk depending on APOE genotype. TOMM40 and PVRL2 genes could interact to substantially increase AD risk, possibly through influencing Aβ metabolism. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Microarray Profile of Long Noncoding RNA and Messenger RNA Expression in a Model of Alzheimer's Disease." The correction includes updated email addresses for two authors and a mistake in Figure 2 of the original publication. The corrected figure shows the chromosome location distribution of upregulated and downregulated long noncoding RNAs. The authors state that the scientific conclusions are unaffected by the error. [Extracted from the article]

We studied how older people describe others with cognitive impairment. Forty-two focus groups represented African Americans, American Indians, Chinese Americans, Latinos, Vietnamese Americans, and Whites other than Latinos (Whites) (N = 396, ages 50+), in nine locations in the United States of America. Axial coding connected categories and identified themes. The constant comparison method compared themes across ethnic groups. African Americans, American Indians and Whites emphasised memory loss. African Americans, American Indians, Latinos and Whites stressed withdrawal, isolation and repetitive speech. African Americans, American Indians, Vietnamese Americans and Whites emphasised ‘slow thinking’. Only Whites described mood swings and personality changes. Many participants attributed dementia to stress. Terms describing others with dementia included ‘Alzheimer's’, ‘dementia’, ‘senile’ and ‘crazy’. Euphemisms were common (‘senior moment’, ‘old timer's disease’). Responses focused on memory, with limited mention of other cognitive functions. Differences among ethnic groups in descriptions of cognitive health and cognitive impairment underscore the need to tailor public health messages about cognitive health to ways that people construe its loss, and to their interest in maintaining it, so that messages and terms used are familiar, understandable and relevant to the groups for which they are designed. Health promotion efforts should develop ethnically sensitive ways to address the widely held misperception that even serious cognitive impairment is a normal characteristic of ageing and also to address stigma associated with cognitive impairment. [ABSTRACT FROM PUBLISHER]

We studied concerns about cognitive health among ethnically diverse groups of older adults. The study was grounded in theories of health behaviour and the representation of health and illness. We conducted 42 focus groups (N=396, ages 50+) in four languages, with African Americans, American Indians, Chinese Americans, Latinos, Whites other than Latinos (hereafter, Whites) and Vietnamese Americans, in nine United States locations. Participants discussed concerns about keeping their memory or ability to think as they age. Audio recordings were transcribed verbatim. Constant comparison methods identified themes. In findings, all ethnic groups expressed concern and fear about memory loss, losing independence, and becoming ‘a burden’. Knowing someone with Alzheimer's disease increased concern. American Indians, Chinese Americans, Latinos and Vietnamese Americans expected memory loss. American Indians, Chinese Americans and Vietnamese Americans were concerned about stigma associated with Alzheimer's disease. Only African Americans, Chinese and Whites expressed concern about genetic risks. Only African Americans and Whites expressed concern about behaviour changes. Although we asked participants for their thoughts about their ability to think as they age, they focused almost exclusively on memory. This suggests that health education promoting cognitive health should focus on memory, but should also educate the public about the importance of maintaining all aspects of cognitive health. [ABSTRACT FROM PUBLISHER]

Abstract: Amyloid-beta peptide (Aβ) is believed to be central in the pathogenesis of Alzheimer''s disease (AD) characterized by cognitive deficits. However, it remains uncertain which form(s) of Aβ pathology is responsible for the cognitive deficits in AD. In the present study, the cognitive deficits and the profiles of Aβ pathology were characterized in the 12-month-old APPswe/PS1dE9 double transgenic mice, and their correlations were examined. Compared with non-transgenic littermates, the middle-aged APPswe/PS1dE9 mice exhibited spatial learning and memory deficits in the water maze test and long-term contextual memory deficits in the step-down passive avoidance test. Among the middle-aged APPswe/PS1dE9 mice, hippocampal soluble Aβ1-40 and Aβ1-42 levels were highly correlated with spatial learning deficits and long-term contextual memory deficits, as well as cortical and hippocampal soluble Aβ1-40 and Aβ1-42 levels were strongly correlated with spatial memory deficits. By contrast, no significant correlations were observed between three measures of cognitive functions and amyloid plaque burden (total Aβ plaque load and fibrillar Aβ plaque load), total Aβ levels (Aβ1-40 and Aβ1-42), as well as insoluble Aβ levels (Aβ1-40 and Aβ1-42). Stepwise multiple regression analysis identified hippocampal soluble Aβ1-40 and Aβ1-42 levels as independent factors for predicting the spatial learning deficits and the long-term contextual memory deficits, as well as hippocampal and cortical soluble Aβ1-40 and Aβ1-42 levels as independent factors for predicting the spatial memory deficits in transgenic mice. These results demonstrate that cognitive deficits are highly related to the levels of soluble Aβ in middle-aged APPswe/PS1dE9 mice, in which soluble Aβ levels are only a tiny fraction of the amount of total Aβ levels. Consequently, our findings provide further evidence that soluble Aβ might primarily contribute to cognitive deficits in AD, suggesting that reducing the levels of soluble Aβ species would be a therapeutic intervention for AD patients even with large deposits of aggregated, insoluble Aβ. [Copyright &y& Elsevier]

Background: Tau pathology is a hallmark of Alzheimer's disease (AD) and other tauopathies. During disease progression, abnormally phosphorylated forms of tau aggregate and accumulate into neurofibrillary tangles, leading to synapse loss, neuroinflammation, and neurodegeneration. Thus, targeting of tau pathology is expected to be a promising strategy for AD treatment.Methods: The effect of rutin on tau aggregation was detected by thioflavin T fluorescence and transmission electron microscope imaging. The effect of rutin on tau oligomer-induced cytotoxicity was assessed by MTT assay. The effect of rutin on tau oligomer-mediated the production of IL-1β and TNF-α in vitro was measured by ELISA. The uptake of extracellular tau by microglia was determined by immunocytochemistry. Six-month-old male Tau-P301S mice were treated with rutin or vehicle by oral administration daily for 30 days. The cognitive performance was determined using the Morris water maze test, Y-maze test, and novel object recognition test. The levels of pathological tau, gliosis, NF-kB activation, proinflammatory cytokines such as IL-1β and TNF-α, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunolabeling, immunoblotting, or ELISA.Results: We showed that rutin, a natural flavonoid glycoside, inhibited tau aggregation and tau oligomer-induced cytotoxicity, lowered the production of proinflammatory cytokines, protected neuronal morphology from toxic tau oligomers, and promoted microglial uptake of extracellular tau oligomers in vitro. When applied to Tau-P301S mouse model of tauopathy, rutin reduced pathological tau levels, regulated tau hyperphosphorylation by increasing PP2A level, suppressed gliosis and neuroinflammation by downregulating NF-kB pathway, prevented microglial synapse engulfment, and rescued synapse loss in mouse brains, resulting in a significant improvement of cognition.Conclusion: In combination with the previously reported therapeutic effects of rutin on Aβ pathology, rutin is a promising drug candidate for AD treatment based its combinatorial targeting of tau and Aβ. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. No disease-modifying strategy to prevent or delay AD progression currently exists. Aβ oligomers (AβOs), rather than monomers or fibrils, are considered as the primary neurotoxic species. Therapeutic approaches that direct against AβOs and promote Aβ clearance may have great value for AD treatment. Results: We here reported a multifunctional superparamagnetic iron oxide nanoparticle conjugated with Aβ oligomer-specific scFv antibody W20 and class A scavenger receptor activator XD4 (W20/XD4-SPIONs). Besides the diagnostic value, W20/XD4-SPIONs retained the anti-Aβ properties of W20 and XD4 by inhibiting Aβ aggregation, attenuating AβO-induced cytotoxicity and increasing microglial phagocytosis of Aβ. When applied to APP/PS1 mice, W20/XD4-SPIONs significantly rescued cognitive deficits and alleviated neuropathology of AD mice. Conclusion: These results suggest that W20/XD4-SPIONs show therapeutic benefits for AD. In combination with the early diagnostic property, W20/XD4-SPIONs present as a promising agent for early-stage AD diagnosis and intervention. [ABSTRACT FROM AUTHOR]

Efficient brain drug delivery has been a challenge in the treatment of Alzheimer's disease (AD) and other brain disorders as blood‐brain barrier (BBB) impedes most drugs to reach brain. To overcome this obstacle, a novel poly(lactic‐co‐glycolic acid) (PLGA) nanoparticle conjugated with CD47 extracellular domain via reactive oxygen species (ROS)‐responsive phenylborate ester bond exhibiting "do not eat me" signal and BBB penetrating peptide CRTIGPSVC (CRT) and microglia modulation agent Nec‐1s encapsulated in it is developed. The experimental results show that the designed nanoparticle efficiently increases its half‐life in blood circulation by preventing engulfment via phagocytes, and enhances its brain distribution by synergistic effect of CD47 and CRT. The high level of ROS in mouse brain releases CD47 from the nanoparticles and the resultant particles are effectively phagocytized by resident microglia. The engulfed Nec‐1s modulates pathological microglia to a beneficial state, which reduces Aβ burden, microgliosis and astrocytosis, decreases cytokine production and oxidative stress in the brains of AD mice, and finally attenuates cognition deficits and synapse loss. The results first demonstrate that the conditionally releasable "do not eat me" CD47 signal remarkably facilitates microglia‐targeted drug delivery and warrants further study to develop therapeutic agent for AD treatment. [ABSTRACT FROM AUTHOR]

Objective: To investigate the role of lncRNA Rpph1 on amyloid-β induced neuronal injury in SK-N-SH cells and underlying mechanism. Methods:In vitro Alzheimer's disease (AD) model was established using the SK-N-SH cells treated with Aβ25-35 peptide. APPswe/PS1ΔE9 double transgenic mice were used as AD animal model. Rpph1 was over-expressed and miR-122 was inhibited or overexpressed in SK-N-SH cells via transfection with pcDNA3.1-oe Rpph1 vector, miR-122 inhibitor or miR-122 mimic, respectively. Cell viabilities and apoptosis were evaluated using MTT or flow cytometry assay, respectively. Quantitative real-time PCR (RT-qPCR) was used to determine expression of Rpph1 and miR-122. Western blotting was used to determine the expression of apoptosis related proteins as well as Wnt/β-catenin signaling related proteins. Dual luciferase reporter assay was conducted to confirm the binding of miR-122 with predictive binding site in 3' UTR of Rpph1 and Wnt1. Results: Both lncRNA Rpph1 and miR-122 were up-regulated in AD mouse. Either over-expression of Rpph1 or inhibition of miR-122 restored the cell viability or decreased cell apoptosis rate in Aβ induced SK-N-SH cells. Overexpression of miR-122 inhibited the cell viability while did not influence the Aβ level in SK-N-SH cells. Furthermore, over-expression of Rpph1, as well as inhibition of miR-122, elevated Bcl-2, c-myc, Survivin and decreased Bax expression via activating Wnt/β-catenin signaling. Dual luciferase reporter assay showed that miR-122 could directly target to 3'UTR of Rpph1 and Wnt1. Conclusion: Both lncRNA Rpph1 and miR-122 were up-regulated in AD mouse and Rpph1 activated Wnt/β-catenin signaling to ameliorate amyloid-β induced neuronal apoptosis in SK-N-SH cells via direct targeting miR-122. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive impairments. Vitegnoside is a flavonoid present in the medicinal plant Vitex negundo, widely used as a folk medicine in several Asian countries including China. It possesses several biological activities, including axon outgrowth, but no evidence is available on its effect on AD. Since no effective treatment is available to cure AD, the effect of vitegnoside on this disease was investigated. The human neuroblastoma SH-SY5Y cell line carrying the Swedish mutation that induces AβPP overexpression was used as an in vitro AD cell model. AβPP overexpression does not induce toxicity per se unless triggered by copper. Vitegnoside promoted neuroprotection through the improvement of cell viability, maintenance of cytomembrane integrity and nuclear homogeneity in these cells, but these effects were not observed in the copper-treated SH-SY5Y cells without AβPP overexpression used as the wild-type control, indicating that vitegnoside exerted neuroprotection under copper-triggered Aβ toxic conditions. Vitegnoside failed to decrease AβPP expression, Aβ40/42 levels, and oxidative stress due to copper-induced Aβ toxicity. However, its administration protected the mitochondrial function and restored the imbalance between pro-apoptotic and anti-apoptotic proteins. Additionally, vitegnoside inactivated p38 MAPK/MK2, JNK/c-Jun, and downstream NF-κB inflammatory transductions. Furthermore, the inactivation of p38 MAPK/JNK signaling contributed to vitegnoside-mediated neuroprotection resulting from pharmacological inhibition of p38 MAPK/JNK and in silico interaction prediction. Our study revealed the neuroprotective effect of vitegnoside and its potential mechanisms against copper-induced Aβ neurotoxicity. These findings highlighted the potential therapeutic effect of vitegnoside against AD progression. [ABSTRACT FROM AUTHOR]

The etiology of late-onset Alzheimer's disease is unknown. Recent epidemiological studies suggest that exposure to high levels of ozone (O 3) may be a risk factor for late-onset Alzheimer's disease. Nonetheless, whether and how O 3 exposure contributes to AD development remains to be determined. In this study, we tested the hypothesis that O 3 exposure synergizes with the genetic risk factor APOE ε4 and aging leading to AD, using male apolipoprotein E (apoE)4 and apoE3 targeted replacement mice as men have increased risk exposure to high levels of O 3 via working environments and few studies have addressed APOE ε4 effects on males. Surprisingly, our results show that O 3 exposure impairs memory in old apoE3, but not old apoE4 or young apoE3 and apoE4, male mice. Further studies show that old apoE4 mice have increased hippocampal activities or expression of some enzymes involved in antioxidant defense, diminished protein oxidative modification, and neuroinflammation following O 3 exposure compared with old apoE3 mice. These novel findings highlight the complexity of interactions between APOE genotype, age, and environmental exposure in AD development. • Cyclic ozone (O 3) exposure impairs memory in old male apolipoprotein E (apoE)3, but not apoE4 , targeted replacement (TR) mice. • Cyclic O 3 exposure has no effect on memory in young male apoE3 or apoE4 TR mice. • O 3 induces severe oxidative stress and neuroinflammation in old male apoE3 mice. • Some antioxidant enzymes are upregulated in the hippocampus of apoE4 male mice. • Old apoE4 mice are resistant to O 3 -induced oxidative stress and neuroinflammation. [ABSTRACT FROM AUTHOR]

Aims Alzheimer's disease (AD) is an incurable neurodegenerative disorder characterized by global cognitive impairment that involves accumulation of amyloid-beta peptides (Aβ) in the brain. Herbal approaches can be used as alternative medicines to slow the progression of AD. This study aimed to determine the beneficial effects and potential underlying mechanisms of total flavonoid extract from Dracoephalum moldavica L. (TFDM) for attenuating Alzheimer-related deficits induced by Aβ. Main methods We used amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice and copper-injured APP Swedish mutation overexpressing SH-SY5Y cells to evaluate the beneficial effects of TFDM. Further, identifying the mechanisms of action was conducted on anti-amyloidogenic and neurotrophic transductions. Key findings Our results indicated that TFDM treatment ameliorated cognitive impairments and neurodegeneration and improved the antioxidant defense system in APP/PS1 mice. TFDM also reduced Aβ burden by relieving Aβ deposition, decreasing insoluble Aβ levels, and inhibiting β-amyloidogenic processing pathway involving downregulation of β-secretase and β-C-terminal fragment in the brain. In the in vitro model of AD, TFDM treatment protected injured cells, and combined with the beneficial effects of decreasing APP levels, lowered Aβ 1–42 and regulated the redox imbalance. Moreover, TFDM preserved the extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor pathway both in vitro and in vivo . Significance In conclusion, TFDM clearly demonstrated neuroprotective effects by restoring the anti-amyloidogenic and neurotrophic transductions in the context of AD-associated deficits. These findings indicate the potential use of herb-based substances as supplements or potential alternative supplements for attenuating the progression of AD. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small noncoding RNAs, which regulate numerous cell functions by targeting mRNA for cleavage or translational repression, and have been found to play an important role in Alzheimer’s disease (AD). Our study aimed to identify differentially expressed miRNAs in AD brain as a reference of potential therapeutic miRNAs or biomarkers for this disease. We used amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice and age-matched wild-type (WT) littermates to determine the expression of miRNAs in the brain. MiRNAs were profiled by microarray, and differentially expressed miRNAs underwent target prediction and enrichment analysis. Microarray analysis revealed 56 differentially expressed miRNAs in AD mouse brain, which involved 39 miRNAs that were significantly upregulated and 19 that were downregulated at different ages. Among those miRNAs, a total of 11 miRNAs, including miR-342-3p, miR-342-5p, miR-376c-3p, and miR-301b-3p, were not only conserved in human but also predicted to have targets and signaling pathways closely related to the pathology of AD. In conclusion, in this study, differentially expressed miRNAs were identified in AD brain and proposed as biomarkers, which may have the potential to indicate AD progression. Despite being preliminary, these results may aid in investigating pathological hallmarks and identify effective therapeutic targets. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by memory loss, intracellular neurofibrillary tangles, and extracellular plaque deposits composed of β-amyloid (Aβ). Previous reports showed that naturally occurring autoantibodies, such as intravenous immunoglobulin (IVIG), benefited patients with moderate-stage AD who carried an APOE-ε4 allele. However, the mechanism underlying the role of IVIG remains unclear. In this study, we identified naturally occurring autoantibodies against Aβ oligomers (NAbs-Aβo), which were purified by Aβ42 oligomer or Cibacron Blue affinity chromatography from IVIG and termed as Oli-NAbs and Blue-NAbs, respectively. Oli-NAbs and Blue-NAbs recognized Aβ42 oligomers or both Aβ40 and 42 oligomers, differently. Both antibodies inhibited Aβ42 aggregation and attenuated Aβ42-induced cytotoxicity. Compared with vehicles, Oli-NAbs, Blue-NAbs and IVIG significantly improved the memory and cognition, and reduced the soluble and oligomeric Aβ levels in APPswe/PS1dE9 transgenic mice. Further investigation showed that Blue-NAbs at increased doses effectively decreased plaque burden and insoluble Aβ levels, whereas Oli-NAbs significantly declined the microgliosis and astrogliosis, as well as the production of proinflammatory cytokines in vivo. Therefore, high levels of these antibodies against oligomeric Aβ40 or Aβ42 were required, correspondingly, to achieve the optimal effect. NAbs-Aβo could be condensed to a high concentration by affinity chromatography and its isolation from IVIG may not interfere with the normal function of conventional IVIG as its concentration is very low. Thus, the isolated NAbs-Aβo as an extra product of plasma required low cost and the enriched NAbs-Aβo may be more feasible than IVIG for the treatment of AD. [ABSTRACT FROM AUTHOR]

The pathologies of Alzheimer's disease (AD) is associated with soluble beta-amyloid (Aβ) oligomers, neuroinflammation and oxidative stress. Decreasing the levels of Aβ oligomer, glial activation and oxidative stress are potential therapeutic approaches for AD treatment. We previously found alpha-tocopherol quinine (α-TQ) inhibited Aβ aggregation and cytotoxicity, decreased the release of inflammatory cytokines and reactive oxygen species (ROS) in vitro . However, whether α-TQ ameliorates memory deficits and other neuropathologies in mice or patients with AD remains unknown. In this study, we reported that orally administered α-TQ ameliorated memory impairment in APPswe/PS1dE9 transgenic mice, decreased oxidative stress and the levels of Aβ oligomer in the brains of mice, prevented the production of inducible nitric oxide synthase and inflammatory mediators, such as interleukin-6 and interleukin-1β, and inhibited microglial activation by inhibiting NF-κB signaling pathway. These findings suggest that α-TQ has potential therapeutic value for AD treatment. [ABSTRACT FROM AUTHOR]

Alzheimer disease (AD) is characterized by extracellular senile plaques, intracellular neurofibrillary tangles, and memory loss. Aggregated amyloid-β (Aβ), oxidative stress, and inflammation have pivotal roles in the pathogenesis of AD. Therefore, the inhibition of Aβ-induced neurotoxicity, oxidative stress, and inflammation is a potential therapeutic strategy for the treatment of AD. In this study, a heptapeptide, isolated from a Ph.D.-C7C library by phage display, attenuated Aβ42-induced cytotoxicity in SH-SY5Y neuroblastoma cells and reduced Aβ42-induced oxidative stress by decreasing the production of reactive oxygen species and glutathione disulfide. As a result, glutathione level increased and superoxide dismutase and glutathione peroxidase activities were enhanced in vitro and in vivo. This peptide also suppressed the inflammatory response by decreasing the release of proinflammatory cytokines, such as tumor necrosis factor α and interleukin 1β, in microglia and by reducing microgliosis and astrogliosis in AD transgenic mice. This peptide was intracerebroventricularly administered to APPswe/PS1dE9 transgenic mice. We found that this peptide significantly improved spatial memory and reduced the amyloid plaque burden and soluble and insoluble Aβ levels. Our findings suggest that this multifunctional peptide has therapeutic potential for an Aβ-targeted treatment of AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) pathogenesis is known to involve a dysregulation of microRNA expression, and these intricate transcriptional cascades between multiple pathological manifestations affect brain homeostasis. Previous studies have revealed that miR-30a-5p participates in neuronal damage and is upregulated in amyloid beta-peptide (Aβ)-induced models. However, its involvement in cognition dysfunction and the AD pathogenic process remains unclear. In the present study, we investigated the mechanisms underlying miR-30a-5p involvement in AD, and its potential as a therapeutic target. Our results reveal that miR-30a-5p was substantially upregulated during the pathological progression of AD, presenting as an increased level in the cortex and hippocampus of APP/PS1 and five familial AD mice, AD cells, and the plasma of AD patients. miR-30a-5p overexpression also induced neuronal injury and apoptosis in AD cells. Mechanistically, miR-30a-5p negatively regulated ADAM10 and SIRT1 by directly binding to their 3′-untranslated regions. A possible association between SIRT1 and ADAM10 was observed via their rescue of miR-30a-5p-induced RARβ downregulation. Interestingly, miR-30a-5p was observed to inhibit the nonamyloidogenic pathway by down regulating ADAM10 and SIRT1, thus promoting Aβ 1–42 overproduction. In APP/PS1 mice, knockdown of miR-30a-5p ameliorated cognitive dysfunctions and neurodegenerative changes, suppressed Aβ accumulation, and inhibited Aβ 1–42 generation by enhancing the nonamyloidogenic pathway via upregulation of ADAM10 and SIRT1. However, these improvements were blocked by ADAM10 and SIRT1 silencing. In conclusion, the present study implicates dysregulation of the miR-30a-5p/ ADAM10/ SIRT1 pathway as a critical mediator of AD pathogenesis, highlighting the importance of epigenetics and identifying novel therapeutic targets in the nonamyloidogenic pathway. [Display omitted] • miR-30a-5p is upregulated during the pathological progression of AD. • miR-30a-5p targets ADAM10 and SIRT1 directly. • miR-30a-5p induces Aβ production via inhibiting the nonamyloidogenic pathway. • The miR-30a-5p/ADAM10/SIRT1 pathway is a potential therapeutic target for AD. [ABSTRACT FROM AUTHOR]

Highlights: [•] Rutin attenuates cognitive impairments in AD transgenic mice. [•] Rutin decreases Aβ oligomer levels in the brains of AD transgenic mice. [•] Rutin reduces oxidative stress, gliosis, and cytokine production in AD mice. [•] Rutin exerts neuro-protective effect on AD transgenic mice. [ABSTRACT FROM AUTHOR]

Abstract: Alzheimer''s disease (AD) is characterized by progressive memory loss due to extracellular senile plaques and intracellular neurofibrillary tangles. The toxic β-amyloid (Aβ) aggregates that form in AD can induce the overproduction of reactive oxygen species (ROS), nitric oxide (NO), and proinflammatory cytokines. These Aβ aggregates likely play a pivotal role in the onset and progression of AD. Reducing Aβ generation, inhibiting Aβ toxicity, and improving Aβ clearance are promising therapeutic strategies for AD. The present paper is the first to reveal a heptapeptide (XD4) isolated from a Ph.D.-C7C library through phage display that significantly inhibited Aβ cytotoxicity, increased the microglial phagocytosis of Aβ, decreased the Aβ-induced generation of ROS and NO, and attenuated the disequilibrium of calcium homeostasis in vitro. Remarkably, XD4 also attenuated memory deficits in β-amyloid precursor protein/presenilin 1 (APPswe/PS1dE9) transgenic mice, and reduced amyloid plaque burden and Aβ40/42 levels. The results of the present study indicate that this peptide, which specifically targets Aβ, may be a promising new therapy for patients exhibiting cognitive impairment and increased Aβ burden. [Copyright &y& Elsevier]

Abstract: Alzheimer''s disease (AD) is a complex, multi-factorial neurodegenerative disease. The aggregation of soluble β-amyloid (Aβ) into fibrillar deposits is a pathological hallmark of AD. The Aβ aggregate-induced neurotoxicity, inflammatory reactions, oxidative stress, and nitric oxide (NO) generation are strongly linked to the etiology of AD. Here, we show that the common dietary flavonoid, rutin, can dose-dependently inhibit Aβ42 fibrillization and attenuate Aβ42-induced cytotoxicity in SH-SY5Y neuroblastoma cells. Moreover, rutin decreases the formation of reactive oxygen species (ROS), NO, glutathione disulfide (GSSG), and malondialdehyde (MDA), reduces inducible nitric oxide synthase (iNOS) activity, attenuates mitochondrial damage, increases the glutathione (GSH)/GSSG ratio, enhances the activities of super oxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), and modulates the production of proinflammatory cytokines by decreasing TNF-α and IL-1β generation in microglia. Taken together, the actions of rutin on multiple pathogenic factors deserves further investigation for the prevention and treatment of AD. [Copyright &y& Elsevier]

Abstract: Increasing evidence indicates that amyloid aggregates, including oligomers, protofibrils or fibrils, are pivotal toxins in the pathogenesis of many amyloidoses such as Alzheimer''s disease (AD), Parkinson''s disease, Huntington''s disease, prion-related diseases, type 2 diabetes and hereditary renal amyloidosis. Various oligomers assembled from different amyloid proteins share common structures and epitopes. Here we present data indicating that two oligomer-specific single chain variable fragment (scFv) antibodies isolated from a naïve human scFv library could conformation-dependently recognize oligomers assembled from α-synuclein, amylin, insulin, Aβ1–40, prion peptide 106–126 and lysozyme, and fibrils from lysozyme. Further investigation showed that both scFvs inhibited the fibrillization of α-synuclein, amylin, insulin, Aβ1–40 and prion peptide 106–126, and disaggregated their preformed fibrils. However, they both promoted the aggregation of lysozyme. Nevertheless, the two scFv antibodies could attenuate the cytotoxicity of all amyloids tested. Moreover, the scFvs recognized the amyloid oligomers in all types of plaques, Lewy bodies and amylin deposits in the brain tissues of AD and PD patients and the pancreas of type 2 diabetes patients respectively, and showed that most amyloid fibril deposits were colocalized with oligomers in the tissues. Such conformation-dependent scFv antibodies may have potential application in the investigation of aggregate structures, the mechanisms of aggregation and cytotoxicity of various amyloids, and in the development of diagnostic and therapeutic reagents for many amyloidoses. [Copyright &y& Elsevier]

Amyloid-β (Aβ40/42) aggregates containing the cross-β-sheet structure are associated with the pathogenesis of Alzheimer's disease (AD). It is generally accepted that the N-terminal peptide of Aβ40/42, Aβ1-16, does not aggregate, and is not cytotoxic. However, we here show that Aβ1-16 can aggregate, and form cytotoxic aggregates containing β-turns and regular non-amyloid β-sheet structures. Factors such as pH, ionic strength, and agitation were found to influence Aβ1-16 aggregation, and the amino acid residues Asp1, His6, Ser8, and Val12 in Aβ1-16 may play a role in this aggregation. Our MTT results showed that Aβ1-16 monomers or oligomers were toxic to SH-SY5Y cells, but Aβ1-16 fibrils exhibited less cytotoxicity. Our studies also indicate that Aβ1-16 aggregates can increase the formation of reactive oxygen species and nitric oxide, induce the loss of calcium homeostasis, and incur the microglial production of TNF-α and IL-4. Thus, our findings suggest that Aβ1-16 may contribute to AD pathogenesis. [ABSTRACT FROM AUTHOR]