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Alzheimer's disease (AD) is the most common form of age‐related dementia, characterized by progressive memory loss and cognitive disturbances. The hippocampus, where adult hippocampal neurogenesis (AHN), a relatively novel form of brain plasticity that refers to the birth of new neurons, occurs, is one of the first brain regions to be affected in AD patients. Recent studies showed that AHN persists throughout life in humans, but it drops sharply in AD patients. Next questions to consider would be whether AHN impairment is a contributing factor to learning and memory impairment in AD and whether restoring AHN could ameliorate or delay cognitive dysfunction. Here, we outline and discuss the current knowledge about the state of AHN in AD patients, AHN impairment as a potentially relevant mechanism underlying memory deficits in AD, therapeutic potential of activating AHN in AD, and the mechanisms of AHN impairment in AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common neurodegenerative disease and, owing to its increasing prevalence, represents one of the leading public health problems in aging populations. The molecular causes underlying the onset and progression of AD are manifold and hitherto still incompletely understood. Research over nearly four decades has clearly delineated genetics to play a crucial role in AD susceptibility, likely in concert with non‐genetic factors. The field has gained considerable momentum and novel insights over the past 10 years owing to the advent and application of high‐throughput genomics technologies in datasets of increasing size. In this contribution to the Mini‐Symposium on the Molecular Etiology of Alzheimer's Disease, we review the current status of genomics research in AD. To this end, we scrutinize and discuss the main findings from the two largest and most current genome‐wide association studies (GWAS) in the field, that is, the papers published by Jansen et al (Nat Genet 51:404–413) and Kunkle et al (Nat Genet 51:414–430). Particular focus is laid on genomics findings overlapping across both studies and on the novel insights they provide in terms of improving our understanding of the "genomic mechanisms" underlying this devastating disease. [ABSTRACT FROM AUTHOR]

Animal models to study Alzheimer's disease (AD) pathogenesis are under development. Since herpesviruses have been postulated to be capable of triggering the pathogenic process, AD animal models (mouse, pig, and non-human primates) should be controlled for the presence of these viruses. Only virus-free models allow studying the genetic factors and the effect of adding viruses. Roseoloviruses such as human herpesvirus 6 and the related viruses in the animals are the main topic of this commentary. [ABSTRACT FROM AUTHOR]

The article discusses the topic of cell aging covered by researcher Elizabeth Blackburn, Ph.D. in her book "The Telomere Effect." Topics mentioned include the estimated number of centenarians who exist around the world, commercial laboratories where people can pay to have their telomerase level analyzed, and a program led by Deepak Chopra, M.D., that included meditation and a variety of Ayurvedic treatments.

The rich and colorful history of gene discovery in Alzheimer's disease (AD) over the past three decades is as complex and heterogeneous as the disease, itself. Twin and family studies indicate that genetic factors are estimated to play a role in at least 80% of AD cases. The inheritance of AD exhibits a dichotomous pattern. On one hand, rare mutations in APP, PSEN1, and PSEN2 are fully penetrant for early-onset (<60 years) familial AD, which represents <5% of AD. On the other hand, common gene polymorphisms, such as the ℇ4 and ℇ2 variants of the APOE gene, influence susceptibility for common (>95%) late-onset AD. These four genes account for 30-50% of the inheritability of AD. Genome-wide association studies have recently led to the identification of additional highly confirmed AD candidate genes. Here, I review the past, present, and future of attempts to elucidate the complex and heterogeneous genetic underpinnings of AD along with some of the unique events that made these discoveries possible. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder with multifaceted neuropathological features, including β-amyloid plaques, neurofibrillary tangles, and neuroinflammation. Over the past decade, emerging evidence has implicated both beneficial and pathological roles for innate immune genes and immune cells, including peripheral immune cells such as T cells, which can infiltrate the brain and either ameliorate or exacerbate AD neuropathogenesis. These findings support a neuroimmune axis of AD, in which the interplay of adaptive and innate immune systems inside and outside the brain critically impacts the etiology and pathogenesis of AD. In this review, we discuss the complexities of AD neuropathology at the levels of genetics and cellular physiology, highlighting immune signaling pathways and genes associated with AD risk and interactions among both innate and adaptive immune cells in the AD brain. We emphasize the role of peripheral immune cells in AD and the mechanisms by which immune cells, such as T cells and monocytes, influence AD neuropathology, including microglial clearance of amyloid-β peptide, the key component of β-amyloid plaque cores, pro-inflammatory and cytotoxic activity of microglia, astrogliosis, and their interactions with the brain vasculature. Finally, we review the challenges and outlook for establishing immune-based therapies for treating and preventing AD. [ABSTRACT FROM AUTHOR]

The genetic underpinnings of Alzheimer's disease (AD) remain largely elusive despite early successes in identifying three genes that cause early-onset familial AD (those that encode amyloid precursor protein (APP) and the presenilins (PSEN1 and PSEN2)), and one genetic risk factor for late-onset AD (the gene that encodes apolipoprotein E (APOE)). A large number of studies that aimed to help uncover the remaining disease-related loci have been published in recent decades, collectively proposing or refuting the involvement of over 500 different gene candidates. Systematic meta-analyses of these studies currently highlight more than 20 loci that have modest but significant effects on AD risk. This Review discusses the putative pathogenetic roles and common biochemical pathways of some of the most genetically and biologically compelling of these potential AD risk factors. [ABSTRACT FROM AUTHOR]

Abstract: Alzheimer''s disease (AD), an insidious and progressive neurodegenerative disorder accounting for the vast majority of dementia, is characterized by global cognitive decline and the robust accumulation of amyloid deposits and neurofibrillary tangles in the brain. This review article is based on the currently published literature regarding molecular studies of AD and the potential involvement of AD neuropathogenesis in post-operative cognitive dysfunction (POCD). Genetic evidence, confirmed by neuropathological and biochemical studies, indicates that excessive β-amyloid protein (Aβ) generated from amyloidogenic processing of the β-amyloid precursor protein (APP) plays a fundamental role in the AD neuropathogenesis. Aβ is produced from APP by β-secretase, and then γ-secretase complex, consisting of presenilins, nicastrin (NCSTN), APH-1 and PEN-2. Additionally, Aβ clearance and APP adaptor proteins can contribute to AD neuropathogenesis via affecting Aβ levels. Finally, cellular apoptosis may also be involved in AD neuropathogenesis. Surgery and anesthesia can cause cognitive disorders, especially in elderly patients. Even the molecular mechanisms underlying these disorders are largely unknown; several perioperative factors such as hypoxia, hypocapnia and anesthetics may be associated with AD and render POCD via trigging AD neuropathogenesis. More studies to assess the potential relationship between anesthesia/surgery and AD dementia are, therefore, urgently needed. [Copyright &y& Elsevier]

Gene defects play a major role in the pathogenesis of degenerative disorders of the nervous system. In fact, it has been the very knowledge gained from genetic studies that has allowed the elucidation of the molecular mechanisms underlying the etiology and pathogenesis of many neurodegenerative disorders. In this review, we discuss the current status of genetic epidemiology of the most common neurodegenerative diseases: Alzheimer disease, Parkinson disease, Lewy body dementia, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington disease, and prion diseases, with a particular focus on similarities and differences among these syndromes. [ABSTRACT FROM AUTHOR]

From Alois Alzheimer's description of Auguste D.'s brain in 1907 to George Glenner's biochemical dissection of β-amyloid in 1984, the "amyloid hypothesis" of Alzheimer's disease has continued to gain support over the past two decades, particularly from genetic studies. Here we assess the amyloid hypothesis based on both known and putative Alzheimer's disease genes. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is a genetically complex and heterogeneous disorder. Fully penetrant (causal) mutations leading to predominantly early-onset familial AD have been identified in three genes (APP, PSEN1, PSEN2), while for the more common late-onset form of the disease, only one partially penetrant genetic risk factor (APOE) has been established to date. Several lines of evidence suggest that additional susceptibility genes exist for both early- and late-onset AD, however, none of the more than three dozen putative AD loci proposed to date have been consistently replicated in follow-up analyses. Novel AD genes will not only provide valuable clues for the development of novel therapeutic approaches, but will also allow the development of new genetic risk profiling strategies that are an essential prerequisite for early prediction/prevention of this devastating disease. This review focuses on the analytic tools used to identify genes in complex diseases, and then provides a summary of recent linkage and association findings indicating the existence of novel late-onset AD genes on several chromosomes. [Copyright &y& Elsevier]

A hallmark of all forms of Alzheimer's disease (AD) is an abnormal accumulation of the β-amyloid protein (Aβ) in specific brain regions. Both the generation and clearance of Aβ are regulated by cholesterol. Elevated cholesterol levels increase Aβ in cellular and most animals models of AD, and drugs that inhibit cholesterol synthesis lower Aβ in these models. Recent studies show that not only the total amount, but also the distribution of cholesterol within neurons, impacts Aβ biogenesis. The identification of a variant of the apolipoprotein E (APOE) gene as a maior genetic risk factor for AD is also consistent with a role for cholesterol in the pathogenesis of AD. Clinical trials have recently been initiated to test whether lowering plasma and/or neuronal cholesterol levels is a viable strategy for treating and preventing AD. In this review, we describe recent findings concerning the molecular mechanisms underlying the cholesterol -- AD connection. [ABSTRACT FROM AUTHOR]

Provides an overview of the complex genetic profile of Alzheimer's disease and discusses the utility of the available genetic tests. Genetics of Alzheimer's disease; Genetic testing for early and late onset of the disease; Summary.

Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer's disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer's disease and their relationships with other Alzheimer's disease and vascular pathologies during this critical early period remain to be elucidated. We included 317 older adults from the Harvard Aging Brain Study, a cohort of individuals who were cognitively unimpaired at baseline and followed longitudinally for up to 12 years. Baseline VEGF family protein levels (VEGFA, VEGFC, VEGFD, PGF and FLT1) were measured in fasting plasma using high-sensitivity immunoassays. Using linear mixed effects models, we examined the interactive effects of baseline plasma VEGF proteins and amyloid PET burden (Pittsburgh Compound-B) on longitudinal cognition (Preclinical Alzheimer Cognitive Composite-5). We further investigated if effects on cognition were mediated by early neocortical tau accumulation (flortaucipir PET burden in the inferior temporal cortex) or hippocampal atrophy. Lastly, we examined the impact of adjusting for baseline cardiovascular risk score or white matter hyperintensity volume. Baseline plasma VEGFA and PGF each showed a significant interaction with amyloid burden on prospective cognitive decline. Specifically, low VEGFA and high PGF were associated with greater cognitive decline in individuals with elevated amyloid, i.e. those on the Alzheimer's disease continuum. Concordantly, low VEGFA and high PGF were associated with accelerated longitudinal tau accumulation in those with elevated amyloid. Moderated mediation analyses confirmed that accelerated tau accumulation fully mediated the effects of low VEGFA and partially mediated (31%) the effects of high PGF on faster amyloid-related cognitive decline. The effects of VEGFA and PGF on tau and cognition remained significant after adjusting for cardiovascular risk score or white matter hyperintensity volume. There were concordant but non-significant associations with longitudinal hippocampal atrophy. Together, our findings implicate low VEGFA and high PGF in accelerating early neocortical tau pathology and cognitive decline in preclinical Alzheimer's disease. Additionally, our results underscore the potential of these minimally-invasive plasma biomarkers to inform the risk of Alzheimer's disease progression in the preclinical population. Importantly, VEGFA and PGF appear to capture distinct effects from vascular risks and cerebrovascular injury. This highlights their potential as new therapeutic targets, in combination with anti-amyloid and traditional vascular risk reduction therapies, to slow the trajectory of preclinical Alzheimer's disease and delay or prevent the onset of cognitive decline. [ABSTRACT FROM AUTHOR]

Focuses on genetic studies and transgenic models of Alzheimer's disease. Clinical syndrome; Neuropathology; Genes influencing Alzheimer's disease; Amyloid precursor protein transgenic mice generated by yeast artificial chromosomes; Transgenic mice generated by microinjection of cDNA constructs of amyloid precursor proteins; Presenilin 1 gene-targeted mice.

Presents a consensus statement from the National Institute on Aging/Alzheimer's Association Working Group on the association between apolipoprotein E (APOE) and risk of Alzheimer's disease (AD). APOE genotyping for AD risk prediction and diagnosis; Ethical, medicolegal, and insurance issues in APOE research; Consensus methodolody; Factors to be taken into account in pre-test counselling for APOE genotyping; Ethical review and oversight of clinical research.

Presents results of a study which investigated the role of genetics in determining life-span. Heritability of life-span; Genetic variants modifying senescence of mammals and invertebrates; Alteration of metabolic pathways; Environmental factors; Gene expression in aging; Genetics of longevity; Genetics of AD and cell death; Alternate life histories.

The risk of Alzheimer disease is substantially influenced by genetic factors. A new genome-wide association study of more than 600,000 individuals identifies nine novel Alzheimer disease risk genes, raising the total count of independent risk loci to 29. [ABSTRACT FROM AUTHOR]

Objectives: Due to increased gene dose for the amyloid precursor protein (APP), elderly adults with Down syndrome (DS) are at a markedly increased risk of Alzheimer's disease (AD), known as DS‐AD. How the increased APP gene dose acts and which APP products are responsible for DS‐AD is not well understood, thus limiting strategies to target pathogenesis. As one approach to address this question, we used a novel class of γ‐secretase modulators that promote γ‐site cleavages by the γ‐secretase complex, resulting in lower levels of the Aβ42 and Aβ40 peptides. Methods: Ts65Dn mice, which serve as a model of DS, were treated via oral gavage with 10 mg/kg/weekday of BPN15606 (a potent and novel pyridazine‐containing γ‐secretase modulators). Treatment started at 3 months‐of‐age and lasted for 4 months. Results: Demonstrating successful target engagement, treatment with BPN15606 significantly decreased levels of Aβ40 and Aβ42 in the cortex and hippocampus; it had no effect on full‐length APP or its C‐terminal fragments in either 2 N or Ts65Dn mice. Importantly, the levels of total amyloid‐β were not impacted, pointing to BPN15606‐mediated enhancement of processivity of γ‐secretase. Additionally, BPN15606 rescued hyperactivation of Rab5, a protein responsible for regulating endosome function, and normalized neurotrophin signaling deficits. BPN15606 treatment also normalized the levels of synaptic proteins and tau phosphorylation, while reducing astrocytosis and microgliosis, and countering cognitive deficits. Interpretation: Our findings point to the involvement of increased levels of Aβ42 and/or Aβ40 in contributing to several molecular and cognitive traits associated with DS‐AD. They speak to increased dosage of the APP gene acting through heightened levels of Aβ42 and/or Aβ40 as supporting pathogenesis. These findings further the interest in the potential use of γ‐secretase modulators for treating and possibly preventing AD in individuals with DS. ANN NEUROL 2024;96:390–404 [ABSTRACT FROM AUTHOR]

The article discusses two genome-wide association studies (GWAS) on Alzheimer's disease (AD). Both studies demonstrated the novel putative susceptibility genes for AD, which includes CLU, CR1 and PICAL. They also discovered the most prominent association was between the risk for AD and the clustering-encoding CLU gene. The authors argue that the identification of novel AD risk genes is relevant to improve the early prediction and prevention of AD.

The article focuses on the latest factor that contribute to Alzheimer's disease. Factors that contribute to the disease include genetic mutations, environmental factors, and the latest factor which is the disease risk gene that is involved in calcium regulation. Increase expression of the gene which is called CALHM1 meaning calcium homeostasis modulator 1, enhances the entry of calcium into the cell and its concentration in the cytoplasm. It is stated that negative-association of polymorphisms with the risks of Alzheimer's disease suggest that CALHM1's road to become an Alzheimer's disease gene could be rutted like the previous candidates.

Examines the synaptic Aβ hypothesis of Alzheimer disease. Role of Aβ in the internalization of NMDA receptors; Molecular mechanism for endocytosis; Role of the accumulation and deposition of fibrillar βamyloid in the neurodegeneration and cognitive decline leading to dementia.

Analyzes the galvanization of beta-amyloid in Alzheimer's disease (AD). Biochemical link between metabolism of amyloid precursor protein and zinc; Therapies for AD; Cause of characteristic amyloid neuropathology of Alzheimer's disease.

This document is a correction notice for an article titled "Palmitoylated APP Forms Dimers, Cleaved by BACE1." The correction addresses errors in the figures and provides updated versions of Fig 1, Fig 2, and Fig 6. The authors also include the original uncropped underlying blots for the figures and the original quantitative data for the article. The correction aims to rectify the errors and provide accurate information to the readers. [Extracted from the article]

It has recently become well-established that there is a connection between Alzheimer's disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aβ deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-dependent manner. In this regard, we were intrigued by the finding that a marine-derived oligosaccharide, GV-971, was reported to alter gut microbiota and reduce Aβ amyloidosis in the 5XFAD mouse model that were treated at a point when Aβ burden was near plateau levels. Utilizing comparable methodologies, but with distinct technical and temporal features, we now report on the impact of GV-971 on gut microbiota, Aβ amyloidosis and microglial phenotypes in the APPPS1-21 model, studies performed at the University of Chicago, and independently in the 5X FAD model, studies performed at Washington University, St. Louis. Methods To comprehensively characterize the effects of GV-971 on the microbiota-microglia-amyloid axis, we conducted two separate investigations at independent institutions. There was no coordination of the experimental design or execution between the two laboratories. Indeed, the two laboratories were not aware of each other's experiments until the studies were completed. Male and female APPPS1-21 mice were treated daily with 40, 80, or 160 mg/kg of GV-971 from 8, when Aβ burden was detectable upto 12 weeks of age when Aβ burden was near maximal levels. In parallel, and to corroborate existing published studies and further investigate sex-related differences, male and female 5XFAD mice were treated daily with 100 mg/kg of GV-971 from 7 to 9 months of age when Aβ burden was near peak levels. Subsequently, the two laboratories independently assessed amyloid-β deposition, metagenomic, and neuroinflammatory profiles. Finally, studies were initiated at the University of Chicago to evaluate the metabolites in cecal tissue from vehicle and GV-971-treated 5XFAD mice. Results These studies showed that independent of the procedural differences (dosage, timing and duration of treatment) between the two laboratories, cerebral amyloidosis was reduced primarily in male mice, independent of strain. We also observed sex-specific microbiota differences following GV-971 treatment. Interestingly, GV-971 significantly altered multiple overlapping bacterial species at both institutions. Moreover, we discovered that GV-971 significantly impacted microbiome metabolism, particularly by elevating amino acid production and influencing the tryptophan pathway. The metagenomics and metabolomics changes correspond with notable reductions in peripheral pro-inflammatory cytokine and chemokine profiles. Furthermore, GV-971 treatment dampened astrocyte and microglia activation, significantly decreasing plaque-associated reactive microglia while concurrently increasing homeostatic microglia only in male mice. Bulk RNAseq analysis unveiled sex-specific changes in cerebral cortex transcriptome profiles, but most importantly, the transcriptome changes in the GV-971-treated male group revealed the involvement of microglia and inflammatory responses. Conclusions In conclusion, these studies demonstrate the connection between the gut microbiome, neuroinflammation, and Alzheimer's disease pathology while highlighting the potential therapeutic effect of GV-971. GV-971 targets the microbiota-microglia-amyloid axis, leading to the lowering of plaque pathology and neuroinflammatory signatures in a sex-dependent manner when given at the onset of Aβ deposition or when given after Aβ deposition is already at higher levels. [ABSTRACT FROM AUTHOR]

Brain spheroids are emerging as valuable in vitro models that are accelerating the pace of research in various diseases. For Alzheimer's disease (AD) research, these models are enhanced using genetically engineered human neural progenitor cells and novel cell culture methods. However, despite these advances, it remains challenging to study the progression of AD in vitro as well as the propagation of pathogenic amyloid-β (Aβ) and tau tangles between diseased and healthy neurons using the brain spheroids model. To address this need, we designed a microfluidic system of connected microwells for arranging two types of brain spheroids in complex patterns and enabling the formation of thick bundles of neurites between the brain spheroids and the accumulation of pathogenic Aβ within the spheroids. [ABSTRACT FROM AUTHOR]

Memory loss is primarily caused by the accumulation of both brain plaques [(consisting of beta-amyloid protein (Aβ) 1–42)] and neurofibrillary tangles (consisting of paired helical and straight filaments containing tau protein). Neuroinflammation is the third key and important factor that leads to accelerated memory loss and eventual dementia. Brain plaques, tangles and inflammation is the trilogy mainly responsible for causing memory loss that has now been documented for over 20 years in the scientific literature. The present investigation used in vitro quantitative methods to directly compare the ability of major memory-support dietary supplements to reduce pre-formed Aβ 1–42 fibrils (21 supplements tested) and tau protein paired helical/straight filaments (13 supplements tested)—two of the three most important targets for memory loss. Additionally, 18 different manufacturers of cat's claw (Uncaria tomentosa) were directly compared for their ability to inhibit/reduce Aβ 1–42 fibrils and/or tau paired helical/straight filaments based on recent findings that PTI-00703 cat's claw is a specific and potent inhibitor/reducer of all three targets -brain plaques, tangles and inflammation (Snow et al. in Sci Rep 9:561, 2019). In the present investigation quantitative Thioflavin T fluorometry was used on a comparative weight-to-weight basis at increasing concentrations with ingredients tested from the actual capsules the consumer ingests. Major memory-support dietary supplements were directly compared for their ability to inhibit and disaggregate/reduce both Aβ 1–42 fibrils and/or tau paired helical/straight filaments. Dietary supplements touted to enhance memory comparatively tested included Prevagen, FOCUSfactor, PROCERA AVH, Alpha Brain, NAD+OVIM, BRAIN JUICE, Cebria, EXCELEROL, NOOCUBE, US Doctor's Clinical Brain Power ADVANCED, healthycell pro, LUMONOL, Brain Awake, BRAIN ARMOR, brainMD (BRAIN & MEMORY POWER BOOST), Brain Support, Clarity (BRAIN HEALTH FORMULA), brainMD (NEUROVITE PLUS), neuriva (Original and Plus) and percepta. This is the first paper to actually comparatively test these memory-support supplements for their ability to reduce Aβ fibrils and tau protein tangles. Percepta (PTI-00703 cat's claw and a specific oolong tea extract) was determined to be the most effective and potent memory support dietary supplement to disaggregate/disrupt Aβ 1–42 fibrils (range of 25–89%) and tau paired helical/straight filaments (range of 26–86%) at all 3–4 doses tested in comparison to other major memory-support dietary supplements tested. This was at least more than double (> 50%) for percepta reducing Aβ 1–42 fibrils and in comparison to the other 20 memory-support dietary supplements tested. The ranking order for memory-support supplement effects based on reducing Aβ 1–42 fibrils (Aβ 1–42: memory-support supplement at 1:0.1 weight-to-weight in a 3-day study) was percepta (69.6% reduction) >>> Alpha Brain (34.9% reduction) = US Doctor's Clinical Brain Power ADVANCED (32.4%) = BRAIN JUICE (30.1%) = neuriva Plus (27%) = neuriva Original (27%) > NEUROVITE PLUS (22.9%) = NOOCUBE (19.9%) = EXCELEROL (17.3%) = healthycell pro (17.2%) > Prevagen (12.9%) > PROCERA AVH (6.5%) = FOCUSfactor (5.5%) > Cebria (0%) = Brain Awake (0%) = Brain Support (0%) = brainMD (BRAIN & MEMORY POWER BOOST) (0%) = NAD+OVIM (0%) = BRAIN ARMOR (0%) = LUMONOL (0%). The ranking order for memory support supplement effects on reducing tau paired helical/straight filaments (tau:memory supplement at 1:1 weight-to-weight at 3 days) was percepta (85.7% reduction) >>> neuriva Plus (57.9%) >> BRAIN JUICE (41.9%) = EXCELEROL (41.0%) = neuriva Original (38.4%) = US Doctor's Clinical Brain Power ADVANCED (38.3%) = healthycell pro (37.6%) >> Alpha Brain (27.9%) >> NOOCUBE (17.6%) >> FOCUSfactor (8.7%) > Cebria (3.6%) = PROCERA AVH (0%) = Prevagen (0%). Congo red staining, Thioflavin S fluorescence, circular dichroism (CD) spectroscopy and electron microscopy confirmed the positive results observed with the supplement percepta. CD spectroscopy demonstrated that percepta caused a marked inhibition of beta-sheet secondary folding of tau protein into paired helical filaments. PTI-00703 cat's claw (main ingredient in percepta) was also identified as the most potent cat's claw bark powder (Uncaria tomentosa) to reduce and inhibit Aβ 1–42 fibrils and tau tangles in comparison to 17 other manufacturers of cat's claw extracts. Although there are thousands of brain memory-support dietary supplements in the marketplace today, none of them have been directly compared and analyzed for their ability to reduce and/or inhibit two major targets of memory loss i.e. Aβ 1–42 fibrils and tau paired helical/straight filaments (major constituents of brain plaques and tangles). In our comparison studies, we show that percepta has the most potent ability to disaggregate/reduce Aβ 1–42 fibrils and tau protein paired helical/straight filaments as demonstrated by a variety of methods most likely due to the specific polyphenol content in PTI-00703 cat's claw (i.e. polyphenols and proanthocyanidins) as we have previously shown (Snow et al. in Sci Rep 9:561, 2019). Memory-support dietary supplements tested that also contained polyphenols and/or cat's claw in their product demonstrated some Aβ fibril and tau protein tangle reducing activity, but were much less effective than percepta. Percepta's main ingredient, PTI-00703 cat's claw, has previously been shown to reduce brain amyloid plaques and Aβ 1–42/40 insoluble/soluble levels in brain (in plaque-producing transgenic mice) with marked concurrent memory improvements (shown by Morris water maze testing) (Snow et al. in Sci Rep 9:561, 2019). The present investigation further confirms that percepta is one of the best dietary supplements that causes a marked reduction and inhibition of Aβ fibrils and tau tangle filaments -two important major targets for memory-support. In addition, PTI-00703 cat's claw was the most effective cat's claw (Uncaria tomentosa) ingredient for reducing /disaggregating and inhibiting Aβ 1–42 fibrils and tau protein paired helical/straight filaments in comparison to 17 other manufacturers of cat's claw extracts tested. [ABSTRACT FROM AUTHOR]

Histone deacetylase 6 (HDAC6) is one of the key histone deacetylases (HDACs) that regulates various cellular functions including clearance of misfolded protein and immunological responses. Considerable evidence suggests that HDAC6 is closely related to amyloid and tau pathology, the two primary hallmarks of Alzheimer's disease (AD). It is still unclear whether HDAC6 expression changes with amyloid deposition in AD during disease progression or HDAC6 may be regulating amyloid phagocytosis or neuroinflammation or other neuropathological changes in AD. In this work, the pathological accumulation of HDAC6 in AD brains over age as well as the relationship of its regulatory activity ‐ with amyloid pathogenesis and pathophysiological alterations is aimed to be enlightened using the newly developed HDAC6 inhibitor (HDAC6i) PB118 in microglia BV2 cell and 3D‐AD human neural culture model. Results suggest that the structure‐based rational design led to biologically compelling HDAC6i PB118 with multiple mechanisms that clear Aβ deposits by upregulating phagocytosis, improve tubulin/microtubule network by enhancing acetyl α‐tubulin levels, regulate different cytokines and chemokines responsible for inflammation, and significantly reduce phospho‐tau (p‐tau) levels associated with AD. These findings indicate that HDAC6 plays key roles in the pathophysiology of AD and potentially serves as a suitable pharmacological target through chemical biology‐based drug discovery in AD. [ABSTRACT FROM AUTHOR]

The development of Alzheimer's disease (AD) drugs has recently witnessed substantial achievement. To further enhance the pool of drug candidates, it is crucial to explore non‐traditional therapeutic avenues. In this study, we present the use of a photolabile curcumin‐diazirine analogue, CRANAD‐147, to induce changes in properties, structures (sequences), and neurotoxicity of amyloid beta (Aβ) species both in cells and in vivo. This manipulation was achieved through irradiation with LED light or molecularly generated light, dubbed as "molecular light", emitted by the chemiluminescence probe ADLumin‐4. Next, aided by molecular chemiluminescence imaging, we demonstrated that the combination of CRANAD‐147/LED or CRANAD‐147/ADLumin‐4 (molecular light) could effectively slow down the accumulation of Aβs in transgenic 5xFAD mice in vivo. Leveraging the remarkable tissue penetration capacity of molecular light, phototherapy employing the synergistic effect of a photolabile Aβ ligand and molecular light emerges as a promising alternative to conventional AD treatment interventions. [ABSTRACT FROM AUTHOR]

The development of Alzheimer's disease (AD) drugs has recently witnessed substantial achievement. To further enhance the pool of drug candidates, it is crucial to explore non‐traditional therapeutic avenues. In this study, we present the use of a photolabile curcumin‐diazirine analogue, CRANAD‐147, to induce changes in properties, structures (sequences), and neurotoxicity of amyloid beta (Aβ) species both in cells and in vivo. This manipulation was achieved through irradiation with LED light or molecularly generated light, dubbed as "molecular light", emitted by the chemiluminescence probe ADLumin‐4. Next, aided by molecular chemiluminescence imaging, we demonstrated that the combination of CRANAD‐147/LED or CRANAD‐147/ADLumin‐4 (molecular light) could effectively slow down the accumulation of Aβs in transgenic 5xFAD mice in vivo. Leveraging the remarkable tissue penetration capacity of molecular light, phototherapy employing the synergistic effect of a photolabile Aβ ligand and molecular light emerges as a promising alternative to conventional AD treatment interventions. [ABSTRACT FROM AUTHOR]

The article offers information on the triggering receptor expressed on myeloid cells 2 protein (TREM2) in relation to Alzheimer's disease. Topics include the role of innate immunity genes on the risk of Alzheimer's disease, the presence of neurofibrillary tangles in the disease, and the Nasu-Hakola disease. It also discusses the impairment of TREM2 recognition of lipid ligands due to the R47H mutation.

Objective: The retromer complex plays an essential role in intracellular endosomal sorting. Deficits in the retromer complex are linked to enhanced Aβ production. The levels of the components of the retromer complex are reported to be downregulated in Alzheimer disease (AD). Down syndrome (DS) shares neuropathological features with AD. Recent evidence points to dysregulation of the retromer complex in DS. The mechanisms underlying retromer deficits in DS and AD are poorly understood. Methods: We measured the levels of retromer components in the frontal cortex of cases of DS‐AD (AD in DS) as well as DS; the frontal cortex of a person partially trisomic (PT‐DS) for human chromosome 21 (HSA21), whose genome had only the normal 2 copies of the APP gene, was also examined. We also analyzed these proteins in the Dp16 mouse model of DS. To further explore the molecular mechanism for changes in the retromer complex, we treated Dp16 mice with a γ‐secretase modulator (GSM; 776890), a treatment that reduces the levels of Aβ42 and Aβ40. Results: We found VPS26A, VPS26B, and VPS29, but not VPS35, were significantly reduced in both DS and DS‐AD, but not in PT‐DS. Downregulation of VPS26A, VPS26B, and VPS29 was recapitulated in the brains of old Dp16 mice (at 16 months of age) and required increased App gene dose. Significantly, GSM treatment completely prevented reductions of the retromer complex. Interpretation: Our studies point to increased APP gene dose as a compromising retromer function in DS and suggest a causal role for Aβ42 and Aβ40. ANN NEUROL 2023;94:245–258 [ABSTRACT FROM AUTHOR]

Gervais et al. suggest that caspase cleavage of amyloid precursor protein (APP) may initiate a feedback loop that produces β-amyloid deposits in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

A calcium-binding protein interacts with the presenilins, modulating their proteolytic processing (pages 1177?1181). [ABSTRACT FROM AUTHOR]

An abstract of the article "Decoding Alzheimer's in the age of genome-wide analyses" by Rudolph E. Tanzi is presented.

Creating a cellular model of Alzheimer's disease (AD) that accurately recapitulates disease pathology has been a longstanding challenge. Recent studies showed that human AD neural cells, integrated into three-dimensional (3D) hydrogel matrix, display key features of AD neuropathology. Like in the human brain, the extracellular matrix (ECM) plays a critical role in determining the rate of neuropathogenesis in hydrogel-based 3D cellular models. Aging, the greatest risk factor for AD, significantly alters brain ECM properties. Therefore, it is important to understand how age-associated changes in ECM affect accumulation of pathogenic molecules, neuroinflammation, and neurodegeneration in AD patients and in vitro models. In this review, mechanistic hypotheses is presented to address the impact of the ECM properties and their changes with aging on AD and AD-related dementias. Altered ECM characteristics in aged brains, including matrix stiffness, pore size, and composition, will contribute to disease pathogenesis by modulating the accumulation, propagation, and spreading of pathogenic molecules of AD. Emerging hydrogel-based disease models with differing ECM properties provide an exciting opportunity to study the impact of brain ECM aging on AD pathogenesis, providing novel mechanistic insights. Understanding the role of ECM aging in AD pathogenesis should also improve modeling AD in 3D hydrogel systems. [ABSTRACT FROM AUTHOR]

Genetic similarity matrices are commonly used to assess population substructure (PS) in genetic studies. Through simulation studies and by the application to whole-genome sequencing (WGS) data, we evaluate the performance of three genetic similarity matrices: the unweighted and weighted Jaccard similarity matrices and the genetic relationship matrix. We describe different scenarios that can create numerical pitfalls and lead to incorrect conclusions in some instances. We consider scenarios in which PS is assessed based on loci that are located across the genome ('globally') and based on loci from a specific genomic region ('locally'). We also compare scenarios in which PS is evaluated based on loci from different minor allele frequency bins: common (>5%), low-frequency (5–0.5%) and rare (<0.5%) single-nucleotide variations (SNVs). Overall, we observe that all approaches provide the best clustering performance when computed based on rare SNVs. The performance of the similarity matrices is very similar for common and low-frequency variants, but for rare variants, the unweighted Jaccard matrix provides preferable clustering features. Based on visual inspection and in terms of standard clustering metrics, its clusters are the densest and the best separated in the principal component analysis of variants with rare SNVs compared with the other methods and different allele frequency cutoffs. In an application, we assessed the role of rare variants on local and global PS, using WGS data from multiethnic Alzheimer's disease data sets and European or East Asian populations from the 1000 Genome Project. [ABSTRACT FROM AUTHOR]

The article presents information on neurofibrillary tangles in Alzheimer's disease. The issue of brain lesions being neurotoxic, protective, or simply incidental has remained controversial. According to a study by researcher T. Gomez-Isla and colleagues, the numbers of neurofibrillary tangles are more closely correlated with neuronal loss and dementia than are the numbers of senile plaques. Another study by researcher K. Santacruz and colleagues suggests that the neurofibrillary tangles observed in the brains of patients with frontotemporal dementia may not cause the dementia. They had assessed the potential for the recovery of brain function during various stages of neurofibrillary abnormalities by deactivating the mutant tau gene.

PILRA (rs1859788 A > G) has been suggested to be a protective variant for Alzheimer's disease (AD) and is an entry co-receptor for herpes simplex virus-1. We conducted a nested case–control study of 360 1:1-matched AD subjects. Interactions between the PILRA-A allele, APOE risk variants (ε3/ε4 or ε4/ε4) and GM17 for AD risk were modelled. The associations were cross-validated using two independent whole-genome sequencing datasets. We found negative interactions between PILRA-A and GM17 (OR 0.72, 95% CI 0.52–1.00) and between PILRA-A and APOE risk variants (OR 0.56, 95% CI 0.32–0.98) in the discovery dataset. In the replication cohort, a joint effect of PILRA and PILRA × GM 17/17 was observed for the risk of developing AD (p.02). Here, we report a negative effect modification by PILRA on APOE and GM17 high-risk variants for future AD risk in two independent datasets. This highlights the complex genetics of AD. [ABSTRACT FROM AUTHOR]

Editorial. Comments on a study by Polvikoski, et al in the November 9, 1995 issue of the `New England Journal of Medicine.' The study's investigation of the relation of the apolipoprotein E genotype to the development of Alzheimer's disease.

Focuses on the development of a transgenic mouse which has neuropathologic features characteristic of those observed in Alzheimer's disease. The Athena mouse strain called platelet-derived growth factor promoter expressing amyloid precursor protein (PDAPP); Implications for research on Alzheimer's disease.

Epigenetic regulation plays substantial roles in human pathophysiology, which provides opportunities for intervention in human disorders through the targeting of epigenetic pathways. Recently, emerging evidence from preclinical studies suggested the potential in developing therapeutics of Alzheimer's disease (AD) by targeting bromodomain containing protein 4 (BRD4), an epigenetic regulatory protein. However, further characterization of AD-related pathological events is urgently required. Here, we investigated the effects of pharmacological degradation or inhibition of BRD4 on AD cell models. Interestingly, we found that both degradation and inhibition of BRD4 by ARV-825 and JQ1, respectively, robustly increased the levels of amyloid-beta (Aβ), which has been associated with the neuropathology of AD. Subsequently, we characterized the mechanisms by which downregulation of BRD4 increases Aβ levels. We found that both degradation and inhibition of BRD4 increased the levels of BACE1, the enzyme responsible for cleavage of the amyloid-beta protein precursor (APP) to generate Aβ. Consistent with Aβ increase, we also found that downregulation of BRD4 increased AD-related phosphorylated Tau (pTau) protein in our 3D-AD human neural cell culture model. Therefore, our results suggest that downregulation of BRD4 would not be a viable strategy for AD intervention. Collectively, our study not only shows that BRD4 is a novel epigenetic component that regulates BACE1 and Aβ levels, but also provides novel and translational insights into the targeting of BRD4 for potential clinical applications. [ABSTRACT FROM AUTHOR]