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Background: Dimebon is a retired non-selective antihistamine drug currently being investigated as a therapeutic agent for the treatment of Alzheimer's disease (AD). Results from several completed clinical trials are mixed and contradictory. Proper interpretations of these clinical observations, as well as future development of dimebon in AD treatment are complicated by the lack of concrete information on the mechanisms by which dimebon might benefit AD. Results: The present studies are designed specifically to assess whether dimebon might modulate β-amyloid (Aβ)-mediated responses which are central to the development and progression of AD dementia. We found that dimebon is bioavailable in the brains of mice following oral administration. AD mice chronically treated with dimebon exhibited a trend of improvement in spatial memory function without affecting the levels of total Ab as well as soluble oligomeric Aβ in the brain. The same trend of behavior improvement is also seen in wild type animals chronically treated with dimebon. Conclusion: Collectively, our preclinical studies using the TgCRND8 AD mouse model demonstrated that dimebon might have some beneficial effect in improving cognitive function independent of Alzheimer's disease-type Abrelated mechanisms or global energy metabolism in the brain. Observations from our study and others suggesting dimebon might improve cognition in wild type mice and rats raises the possibility that dimebon might be able to benefit cognitive function in patients with other neurodegenerative disorders, such as Huntington's disease, or in the aging population. Additional studies will be necessary to clarify the mechanisms by which dimebon might directly or indirectly benefit cognitive function. [ABSTRACT FROM AUTHOR]

BACE1 (β-secretase) plays a central role in the β-amyloidogenesis of Alzheimer's disease (AD). The ubiquitin-proteasome system, a major intracellular protein quality control system, has been implicated recently in BACE1 metabolism. We report that the SCF-E3 ligase is involved in the binding and ubiquitination of BACE1 via its Trp 280 residue of F-box-associated domain. Physiologically, we found that Fbx2 was expressed in various intracellular organelles in brain neurons and that BACE1 is colocalized with Fbx2 and the amyloid precursor protein (APP), mainly at the early endosome and endoplasmic reticulum. The former are believed to be the major intracellular compartments where the APP is cleaved by BACE1 and β-amyloid is produced. Importantly, we found that overexpression of Fbx2 in the primary cortical and hippocampal neurons derived from Tg2576 transgenic mice significantly promoted BACE1 degradation and reduced β-amyloid production. In the search for specific endogenous modulators of Fbx2 expression, we found that PPARγ coactivator-1α (PGC-1α) was capable of promoting the degradation of BACE1 through a mechanism involving Fbx2 gene expression. Interestingly, we found that the expression of both Fbx2 and PGC-1α was significantly decreased in the brains of aging Tg2576 mice. Our in vivo studies using a mouse model of AD revealed that exogenous adenoviral Fbx2 expression in the brain significantly decreased BACE1 protein levels and activity, coincidentally reducing β-amyloid levels and rescuing synaptic deficits. Our study is the first to suggest that promoting Fbx2 in the brain may represent a novel strategy for the treatment of AD. [ABSTRACT FROM AUTHOR]

Drosophila models of tauopathies have been developed by transgenically overexpressing the disease-associated forms of tau. In this paper we report for the first time that a recently developed Grape-Seed Polyphenolic Extract (GSPE) improves the eye phenotype of a Drosophila eye model of R406W tau. GSPE-mediated improvements in this distinct in vivo neurodegeneration model for protein misfolding/aggregation suggest that GSPE may have therapeutic value in disorders involving aberrant protein aggregation. [ABSTRACT FROM AUTHOR]

Objectives: To explore mechanisms through which altered peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) expression may influence Alzheimer disease (AD) amyloid neuropathology and to test the hypothesis that promotion of PGC-1α expression in neurons might be developed as a novel therapeutic strategy in AD. Design: Case-control. Patients: Human postmortem brain (hippocampal formation) samples from AD cases and age-matched non-AD cases. Results: Using genome-wide complementary DNA microarray analysis, we found that PGC-1α messenger RNA expression was significantly decreased as a function of progression of clinical dementia in the AD brain. Following confirmatory real-time polymerase chain reaction assay, we continued to explore the role of PGC-1α in clinical dementia and found that PGC-1α protein content was negatively associated with both AD-type neuritic plaque pathology and β-amyloid (Aβ)X-42 contents. Moreover, we found that the predicted elevation of amyloidogenic Aβ1-42 and Aβ1-40 peptide accumulation in embryonic cortico-hippocampal neurons derived from Tg2576 AD mice under hyperglycemic conditions (glucose level, 182-273 mg/dL) coincided with a dosedependent attenuation in PGC-1α expression. Most importantly, we found that the reconstitution of exogenous PGC-1α expression in Tg2576 neurons attenuated the hyperglycemic-mediated β-amyloidogenesis through mechanisms involving the promotion of the "nonamyloidogenic" α-secretase processing of amyloid precursor protein through the attenuation of the forkheadlike transcription factor 1 (FoxO3a) expression. Conclusion: Therapeutic preservation of neuronal PGC-1α expression promotes the nonamyloidogenic processing of amyloid precursor protein precluding the generation of amyloidogenic Aβ peptides. [ABSTRACT FROM AUTHOR]

Recent studies suggest that certain cardiovascular antihypertensive agents decrease the incidence of Alzheimer's disease. Based on this evidence and the fact that Aβ aggregation into high-molecular-weight-soluble oligomeric Aβ species is known to directly induce cognitive impairment, we tested the possibility that certain antihypertensive compounds may affect the progression of Alzheimer's disease, at least in part by influencing the formation of Aβ oligomers. High throughput screening of 55 commercially available antihypertensive drugs identified four compounds that significantly reduced Aβ_{1-42} oligomerization in a dose dependent manner. These four compounds, furosemide (diuretic), nitrendipine (calcium channel blocker), candesartan cilextil (angiotensin II receptor antagonist) and diazoxide (vasodilator) showed no detectable Aβ lowering activities in primary neuron cultures generated from Tg2576 mouse embryos. However, furosemide, nitrendipine and candesartan cilextil prevented oligomerization of both Aβ_{1-40} and Aβ_{1-42} in vitro. Furosemide also dissociated pre-aggregated Aβ_{1-42} oligomers. Furthermore, short term furosemide treatment resulted in decreased amount of Aβ oligomers in the brain of Tg2576 mice. Our studies suggest that certain antihypertensive compounds may prevent AD-type neuropathology through inhibition of Aβ oligomer formation. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive impairments in memory and cognition. Extracellular accumulation of soluble high-molecular-weight (HMW) Aβ oligomers has been proposed to be largely responsible for AD dementia and memory deficits in the Tg2576 mice, a model of AD. In this study, we found that a naturally derived grape seed polyphenolic extract can significantly inhibit amyloid β-protein aggregation into high-molecular-weight oligomers in vitro. When orally administered to Tg2576 mice, this polyphenolic preparation significantly attenuates AD-type cognitive deterioration coincidentally with reduced HMW soluble oligomeric Aβ in the brain. Our study suggests that grape seed-derived polyphenolics may be useful agents to prevent or treat AD. [ABSTRACT FROM AUTHOR]

Background: The cause of neuronal death in amyotrophic lateral sclerosis (ALS) is uncertain but mitochondrial dysfunction may play an important role. Ketones promote mitochondrial energy production and membrane stabilization. Results: SOD1-G93A transgenic ALS mice were fed a ketogenic diet (KD) based on known formulations for humans. Motor performance, longevity, and motor neuron counts were measured in treated and disease controls. Because mitochondrial dysfunction plays a central role in neuronal cell death in ALS, we also studied the effect that the principal ketone body, D-β-3 hydroxybutyrate (DBH), has on mitochondrial ATP generation and neuroprotection. Blood ketones were > 3.5 times higher in KD fed animals compared to controls. KD fed mice lost 50% of baseline motor performance 25 days later than disease controls. KD animals weighed 4.6 g more than disease control animals at study endpoint; the interaction between diet and change in weight was significant (p = 0.047). In spinal cord sections obtained at the study endpoint, there were more motor neurons in KD fed animals (p = 0.030). DBH prevented rotenone mediated inhibition of mitochondrial complex I but not malonate inhibition of complex II. Rotenone neurotoxicity in SMI-32 immunopositive motor neurons was also inhibited by DBH. Conclusion: This is the first study showing that diet, specifically a KD, alters the progression of the clinical and biological manifestations of the G93A SOD1 transgenic mouse model of ALS. These effects may be due to the ability of ketone bodies to promote ATP synthesis and bypass inhibition of complex I in the mitochondrial respiratory chain. [ABSTRACT FROM AUTHOR]

Early diagnosis of Alzheimer's disease (AD) and the identification of significant risk factors are necessary to better understand disease progression, and to develop intervention-based therapies prior to significant neurodegeneration. There is thus a critical need to establish biomarkers which can predict the risk of developing AD before the onset of cognitive decline. A number of studies have indicated that exposure to various microbial pathogens can accelerate AD pathology. Additionally, several studies have indicated that amyloid-β possess antimicrobial properties and may act in response to infection as a part of the innate immune system. These findings have led some to speculate that certain types of infections may play a significant role in AD pathogenesis. In this review, we will provide an overview of studies which suggest pathogen involvement in AD. Additionally, we will discuss a number of pathogen-associated biomarkers which may be effective in establishing AD risk. Infections that increase the risk of AD represent a modifiable risk factor which can be treated with therapeutic intervention. Pathogen-based biomarkers may thus be a valuable tool for evaluating and decreasing AD risk across the population. [ABSTRACT FROM AUTHOR]

The aggregation and accumulation of amyloid-β plaques and tau proteins in the brain have been central characteristics in the pathophysiology of Alzheimer's disease (AD), making them the focus of most of the research exploring potential therapeutics for this neurodegenerative disease. With success in interventions aimed at depleting amyloid-β peptides being limited at best, a greater understanding of the physiological role of amyloid-β peptides is needed. The development of amyloid-β plaques has been determined to occur 10–20 years prior to AD symptom manifestation, hence earlier interventions might be necessary to address presymptomatic AD. Furthermore, recent studies have suggested that amyloid-β peptides may play a role in innate immunity as an antimicrobial peptide. These findings, coupled with the evidence of pathogens such as viruses and bacteria in AD brains, suggests that the buildup of amyloid-β plaques could be a response to the presence of viruses and bacteria. This has led to the foundation of the antimicrobial hypothesis for AD. The present review will highlight the current understanding of amyloid-β, and the role of bacteria and viruses in AD, and will also explore the therapeutic potential of antimicrobial and antiviral drugs in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

As a consequence of the considerable increase in the human lifespan over the last century, we are experiencing the appearance and impact of new age-related diseases. The causal relationships between aging and an enhanced susceptibility of suffering from a broad spectrum of diseases need to be better understood. However, one specific shared feature seems to be of capital relevance for most of these conditions: the low-grade chronic inflammatory state inherently associated with aging, i.e., inflammaging. Here, we review the molecular and cellular mechanisms that link aging and inflammaging, focusing on the role of the innate immunity and more concretely on the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, as well as how the chronic activation of this inflammasome has a detrimental effect on different age-related disorders. [ABSTRACT FROM AUTHOR]

The aggregation and deposition of α-synuclein (αS) are major pathologic features of Parkinson's disease, dementia with Lewy bodies, and other α-synucleinopathies. The propagation of αS pathology in the brain plays a key role in the onset and progression of clinical phenotypes. Thus, there is increasing interest in developing strategies that attenuate αS aggregation and propagation. Based on cumulative evidence that αS oligomers are neurotoxic and critical species in the pathogenesis of α-synucleinopathies, we and other groups reported that phenolic compounds inhibit αS aggregation including oligomerization, thereby ameliorating αS oligomer-induced cellular and synaptic toxicities. Heterogeneity in gut microbiota may influence the efficacy of dietary polyphenol metabolism. Our recent studies on the brain-penetrating polyphenolic acids 3-hydroxybenzoic acid (3-HBA), 3,4-dihydroxybenzoic acid (3,4-diHBA), and 3-hydroxyphenylacetic acid (3-HPPA), which are derived from gut microbiota-based metabolism of dietary polyphenols, demonstrated an in vitro ability to inhibit αS oligomerization and mediate aggregated αS-induced neurotoxicity. Additionally, 3-HPPA, 3,4-diHBA, 3-HBA, and 4-hydroxybenzoic acid significantly attenuated intracellular αS seeding aggregation in a cell-based system. This review focuses on recent research developments regarding neuroprotective properties, especially anti-αS aggregation effects, of phenolic compounds and their metabolites by the gut microbiome, including our findings in the pathogenesis of α-synucleinopathies. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder manifesting with upper and lower neuron loss, leading to impairments in voluntary muscle function and atrophy. Mitochondrial dysfunction in metabolism and morphology have been implicated in the pathogenesis of ALS, including atypical oxidative metabolism, reduced mitochondrial respiration in muscle, and protein aggregates in the mitochondrial outer membrane. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) plays an essential role in the regulation of mitochondrial biogenesis, the process by which existing mitochondria grow and divide. PGC-1α has been previously reported to be downregulated in the spinal cord of individuals with ALS. Towards targeting PGC-1α as a therapeutic mechanism, we have previously reported improved motor function and survival in the SOD1G93A mouse model of ALS by neuron-specific over-expression of PGC-1α under a neuron-specific enolase (NSE) promoter. As pharmacological intervention targeting PGC-1α would result in whole-body upregulation of this transcriptional co-activator, in the current study we investigated whether global expression of PGC-1α is beneficial in a SOD1G93A mouse model, by generating transgenic mice with PGC-1α transgene expression driven by an actin promoter. Actin-PGC-1α expression levels were assayed and confirmed in spinal cord, brain, muscle, liver, kidney, and spleen. To determine the therapeutic effects of global expression of PGC-1α, wild-type, actin-PGC-1α, SOD1G93A, and actin-PGC-1α/SOD1G93A animals were monitored for weight loss, motor performance by accelerating rotarod test, and survival. Overexpression of actin-PGC-1α did not confer significant improvement in these assessed outcomes. A potential explanation for this difference is that the actin promoter may not induce levels of PGC-1α relevant to disease pathophysiology in the cells that are specifically relevant to the pathogenesis of ALS. This evidence strongly supports future therapeutic approaches that target PGC-1α primarily in neurons. [ABSTRACT FROM AUTHOR]

Dietary polyphenols promote memory in models of sleep deprivation (SD), stress, and neurodegeneration. The biological properties of dietary polyphenols greatly depend upon the bioavailability of their phenolic metabolites derivatives, which are modulated by gut microbiota. We recently demonstrated that supplementation with grape-derived bioactive dietary polyphenol preparation (BDPP) improves SD-induced cognitive impairment. This study examined the role of the gut microbiota in the ability of BDPP to prevent memory impairment in response to SD. C57BL6/J mice, treated with antibiotics mix (ABX) or BDPP or both, were sleep-deprived at the end of a fear conditioning training session and fear memory was assessed the next day. Gut microbiota composition was analyzed in fecal samples and BDPP-driven phenolic acid metabolites extraction was measured in plasma. We report that the beneficial effect of BDPP on memory in SD is attenuated by ABX-induced dysbiosis. We identified specific communities of fecal microbiota that are associated with the bioavailability of BDPP-derived phenolic acids, which in turn, are associated with memory promotion. These results suggest the gut microbiota composition significantly affects the bioavailability of phenolic acids that drive the dietary polyphenols' cognitive resilience property. Our findings provide a preclinical model with which to test the causal association of gut microbiota-polyphenols, with the ultimate goal of potential developing dietary polyphenols for the prevention/treatment of cognitive impairment. [ABSTRACT FROM AUTHOR]

Grape-derived polyphenols have been investigated for their role in promoting memory in model systems of stress, but little is known about select subpopulations of neurons that are influenced by polyphenols to improve memory performance. Granule neurons in the hippocampal dentate gyrus are vulnerable to stressors that impair contextual memory function and can be influenced by dietary polyphenols. We utilized a c-fos-tTA/TRE-ChR2 optogenetics model in which neurons activated during fear learning are labeled with ChR2-mCherry and can be optically reactivated in a different context to recapitulate the behavioral output of a related memory. Treatment with dietary polyphenols increased fear memory recall and ChR2-mCherry expression in dentate gyrus neurons, suggesting that dietary polyphenols promote recruitment of neurons to a fear memory engram. We show that dietary polyphenols promote memory function and offer a general method to map cellular subpopulations influenced by dietary polyphenols, in part through the mechanism of c-Fos expression enhancement. Chad Smith et al. show that dietary polyphenols, compounds found in grapes, enable mice to remember fearful events more effectively and map this function to the hippocampal dentate gyrus neurons. This study offers a way to identify the cellular subpopulations regulated by dietary polyphenols. [ABSTRACT FROM AUTHOR]

[Display omitted] • Female mice exhibit persistent depression-like behavior during post-stress period after exposure to chronic stress. • Persistent depression-like behavior in female mice linked to changes in morphology and activated phagocytic microglia. • Toll-like receptor 4 signaling in activated microglia is a key mechanism for persistent depression-like behavior in female mice. Chronic stress is a major risk factor for Major Depressive Disorder (MDD), and it has been shown to impact the immune system and cause microglia activation in the medial prefrontal cortex (mPFC) involved in the pathogenesis of depression. The aim of this study is to further investigate cellular and molecular mechanisms underlying persistent depression behavior in sex specific manner, which is observed clinically. Here, we report that both male and female mice exhibited depression-like behavior following exposure to chronic stress. However, only female mice showed persistent depression-like behavior, which was associated with microglia activation in mPFC, characterized by distinctive alterations in the phenotype of microglia. Given these findings, to further investigate the underlying molecular mechanisms associated with persistent depression-like behavior and microglia activation in female mice, we used translating-ribosome affinity purification (TRAP). We find that Toll like receptor 4 (TLR4) signaling is casually related to persistent depression-like behavior in female mice. This is supported by the evidence that the fact that genetic ablation of TLR4 expression in microglia significantly reduced the persistent depression-like behavior to baseline levels in female mice. This study tentatively supports the hypothesis that the TLR4 signaling in microglia may be responsible for the sex differences in persistent depression-like behavior in female. [ABSTRACT FROM AUTHOR]

There are a number of potential implications for the field of Alzheimer's disease (AD) stemming from the global spread of SARS-CoV-2. Neuroinflammation is known to be a prominent feature of neurodegeneration and plays a major role in AD pathology. Immune response and excessive inflammation in COVID-19 may also accelerate the progression of brain inflammatory neurodegeneration, and elderly individuals are more susceptible to severe outcomes after SARS-CoV-2 infection. Individuals with type 2 diabetes (T2D) are at an increased risk for AD as well as severe outcomes after SARS-CoV-2 infection. Genetic and socioeconomic factors influencing the rates of T2D, AD, and COVID-19 severity may create an exceptionally high-risk profile for certain demographics such as African Americans and Hispanic Americans. Type I interferon response plays an important role in both host response to viral infection, as well as AD pathology and may be a sensible therapeutic target in both AD and COVID-19. [ABSTRACT FROM AUTHOR]

Dysfunctional immune activity is a physiological component of both Alzheimer's disease (AD) and major depressive disorder (MDD). The extent to which altered immune activity influences the development of their respective cognitive symptoms and neuropathologies remains under investigation. It is evident, however, that immune activity affects neuronal function and circuit integrity. In both disorders, alterations are present in similar immune networks and neuroendocrine signalling pathways, immune responses persist in overlapping neuroanatomical locations, and morphological and structural irregularities are noted in similar domains. Epidemiological studies have also linked the two disorders, and their genetic and environmental risk factors intersect along immune-activating pathways and can be synonymous with one another. While each of these disorders individually contains a large degree of heterogeneity, their shared immunological components may link distinct phenotypes within each disorder. This review will therefore highlight the shared immune pathways of AD and MDD, their overlapping neuroanatomical features, and previously applied, as well as novel, approaches to pharmacologically manipulate immune pathways, in each neurological condition. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc. [ABSTRACT FROM AUTHOR]