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Molecular Signatures Underlying Selective Regional Vulnerability to Alzheimer's Disease

ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive cognitive impairment and neurodegeneration as a result of abnormal neuronal loss. To elucidate the molecular systems associated with AD, we characterized the gene expression changes associated with multiple clinical and neuropathological traits in 1,053 postmortem brain samples across 19 brain regions from 125 persons dying with varying severities of dementia and variable AD-neuropathology severities. 125 human brains were accessed from the Mount Sinai/JJ Peters VA Medical Center Brain Bank (MSBB). This brain resource was assembled after applying stringent inclusion/exclusion criteria and represents the full spectrum of clinical and neuropathological disease severity in the absence of discernable non-AD neuropathology. RNA samples from 19 brain regions isolated from the 125 MSBB specimens were collected and profiled using Affymetrix Genechip microarrays. There were 50 to 60 subjects per brain region with varying degrees of AD pathological abnormalities.

ORGANISM(S): Homo sapiens

SUBMITTER: Bin Zhang

PROVIDER: E-GEOD-84422 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Molecular Signatures Underlying Selective Regional Vulnerability to Alzheimer's Disease

Project description:Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive cognitive impairment and neurodegeneration as a result of abnormal neuronal loss. To elucidate the molecular systems associated with AD, we characterized the gene expression changes associated with multiple clinical and neuropathological traits in 1,053 postmortem brain samples across 19 brain regions from 125 persons dying with varying severities of dementia and variable AD-neuropathology severities.

2016-08-19 | GSE84422 | GEO

Fetal malformations and early embryonic gene expression response in Cynomolgus monkeys maternally exposed to thalidomide

Project description:EXPERIMENT: The animal experiments were performed at Shin Nippon Biomedical Laboratories (SNBL), Ltd. (Kagoshima, Japan) in compliance with the Guideline for Animal Experimentation (1987), and in accordance with the Law Concerning the Protection and Control of Animals (1973) and the Standards Relating to the Care and Management of Experimental Animals (1980). This study was approved by the Institutional Animal Care and Use Committee of SNBL and performed in accordance with the ethics criteria contained in the bylaws of the SNBL committee. Each female monkey was paired with a male of proven fertility for one day between day 11 and day 15 of the menstrual cycle. Pregnant females, aged 5-8 years and weighing 2.84-3.76 kg on day 22 of gestation, were allocated randomly to two groups, each with three monkeys, and housed individually. The monkeys were orally dosed with (Â±)-thalidomide (Lot no. SDH7273/SDJ3347, Wako Pure Chemical Industries, Ltd., Osaka, Japan) at 0 or 20 mg/kg by oral intubation on day 26 of gestation, which was during the critical period for thalidomide-induced teratogenesis [Delahunt and Lassen, 1964; Hendrickx, 1973]. Dosage was adjusted to the body weight on day 22 of gestation and the drug was packed in a gelatin capsule. Control monkeys received the capsule only. ANIMAL MODEL: Macaca fascicularis INTERVAL: NON. PLATFORM: Proprietary Affymetrix NHP GeneChipÂ® Array for Cynomolgus genome derived from Biogen Idec Keywords = Developmental Keywords = Monkeys Keywords = Thalidomide TFetal malformations and early embryonic gene expression response in cynomolgus monkeys maternally exposed to thalidomidechannel oligonucleotide (Affymetrix) platform.

2010-06-20 | E-GEOD-15542 | biostudies-arrayexpress

Cross-tissue methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer’s disease neuropathology

Project description:Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that is characterized by progressive neuropathology and cognitive decline. We performed a cross-tissue analysis of methylomic variation in AD using samples from three independent human post-mortem brain cohorts. We identified a differentially methylated region in the ankyrin 1 (ANK1) gene that was associated with neuropathology in the entorhinal cortex, a primary site of AD manifestation. This region was confirmed as being substantially hypermethylated in two other cortical regions (superior temporal gyrus and prefrontal cortex), but not in the cerebellum, a region largely protected from neurodegeneration in AD, or whole blood obtained pre-mortem from the same individuals. Neuropathology-associated ANK1 hypermethylation was subsequently confirmed in cortical samples from three independent brain cohorts. This study represents, to the best of our knowledge, the first epigenome-wide association study of AD employing a sequential replication design across multiple tissues and highlights the power of this approach for identifying methylomic variation associated with complex disease. For the first (discovery) stage of our analysis, we used multiple tissues from donors (N = 122) archived in the MRC London Brainbank for Neurodegenerative Disease. From each donor, we isolated genomic DNA from four brain regions (EC, superior temporal gyrus (STG), prefrontal cortex (PFC) and CER) and, where available, from whole blood obtained pre-mortem. Our analyses focused on identifying differentially methylated positions (DMPs) associated with Braak staging, a standardized measure of neurofibrillary tangle burden determined at autopsy.

2014-08-17 | E-GEOD-59685 | biostudies-arrayexpress

Cortical hypermethylation across an extended region spanning the HOXA gene cluster on chromosome 7 is robustly associated with Alzheimer's disease neuropathology

Project description:Alzheimer's disease is a progressive neurodegenerative disorder that is hypothesized to involve epigenetic dysfunction. We undertook an epigenome-wide association study across three independent brain tissue cohorts (total n = 999) to identify differential DNA methylation associated with neuropathology in the superior temporal gyrus and prefrontal cortex. We present robust evidence for elevated DNA methylation associated with AD neuropathology across an extended region spanning the HOXA gene cluster on chromosome 7. Prefrontal cortex and superior temporal gyrus tissue from 147 individuals with varying levels of AD pathology. DNA modifications for these samples were quantified using the Illumina Infinium Human 450K Methylation Array.

2016-08-01 | E-GEOD-80970 | biostudies-arrayexpress

Genome-wide H3K27ac profiles in post-mortem entorhinal cortex samples from Alzheimer's disease cases and controls

Project description:We quantified genome-wide levels of H3K27ac in post-mortem entorhinal cortex tissue samples, identifying widespread Alzheimer's disease (AD)-associated acetylomic variation. Differentially acetylated peaks were identified in the vicinity genes implicated in both tau and amyloid neuropathology (MAPT, APP, PSEN1, PSEN2), as well as genomic regions containing variants associated with sporadic late-onset AD (CR1, TOMM40). Both MAPT and PSEN2 are characterized by an extended hyperacetylated region upstream of the TSS mapping to enhancers in the brain. We show that genes annotated to AD-associated hyper- and hypoacetylated peaks are enriched for brain- and neuropathology-related functions.

2018-08-11 | GSE102538 | GEO

Cross-tissue methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer’s disease neuropathology

2014-08-17 | GSE59685 | GEO

Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease

Project description:Astrocytes are crucial to brain homeostasis, yet their changes along the spatiotemporal progression of Alzheimer’s disease (AD) neuropathology remain largely unexplored. Here, we performed single- nucleus RNA-sequencing of 628,943 astrocytes from five brain regions representing the stereotypical progression of AD pathology, across 32 donors spanning the entire normal aging-to-severe AD continuum. We discovered astrocyte gene expression trajectories that are differentially activated or suppressed at various regions and disease stages. We mapped out several unique astrocyte subclusters that exhibited varying responses to neuropathology across the AD-vulnerable neural network (spatial axis) or AD pathology stage (temporal axis). The proportion of homeostatic, intermediate, and reactive astrocytes changed solely along the spatial axis, whereas two other unique subclusters changed along the temporal axis. One of these, a trophic factor-rich subcluster, declined along pathology stage, whereas the other, defined by proteostasis and metabolic genes, increased in late-stage but unexpectedly returned to baseline levels in end-stage, suggesting exhaustion of response with chronic exposure to neuropathology. Our study underscores the complex and dynamic nature of astrocytic responses in AD and our findings are available at https://ad-progression-atlas.partners.org

2024-07-22 | GSE268599 | GEO

Transcriptomic analysis of probable asymptomatic and symptomatic Alzheimer Brains

Project description:Objectives: Individuals with intact cognition and neuropathology consistent with Alzheimer’s disease (AD) are referred to as asymptomatic AD (AsymAD). These individuals are highly likely to develop AD, yet transcriptomic changes in the brain which might reveal mechanisms for their AD vulnerability are currently unknown. Methods: Differential and co-expression analysis was performed on microarray profiled human brains of 27 control , 33 AsymAD and 52 AD subjects. Tissues known to be affected by AD neuropathology (entorhinal cortex, temporal cortex, frontal cortex) and tissue partially spared by the disease (cerebellum). Results: The AsymAD subjects exhibited significant changes in transcriptomic activity in the frontal cortex when compared to AD and control subjects. Fourteen genes (GPM6B, ANKEF1, NPC2, ALDH2, FBLN2, METTL7A, FLCN, ASPHD1, ARL5A, GPR162, HBA2, PCID2, BEND3 and RAP1Gap) were highly associated with AD neuropathology with overall disturbances in the “glutamate-glutamine cycle”, “oxidative phosphorylation”, “innate immune system”, “TYROBP network”, “neutrophil degranulation” and “amino acid metabolism” in both the AsymAD and AD subjects. Conclusions: Transcriptomic activity in AsymAD subjects suggests fundamental changes in AD brains may begin within the frontal cortex region. In addition, we provide new insight into the earliest biological changes occurring in the brain prior to clinical AD diagnosis which offers new avenues for therapeutic interventions for preventing AD. We provide access of gene-level results to the broader research community through a publicly available R SHINY web-application accessible at: https://phidatalab-shiny.rosalind.kcl.ac.uk/ADbrainDE

2019-07-22 | GSE118553 | GEO

Age- and ApoE genotype-dependent transcriptomic responses to O3 in the hippocampus of mice

Project description:We earlier demonstrated that ozone an urban pollutant, accelerates AD-like neuropathology in aging male ApoE3 mice. In this study, we investigate hippocampal transcriptomic alterations in young and aged E3 and E4 mice following O₃ exposure to elucidate the molecular mechanisms underlying O₃-induced AD pathology specifically in old E3 male mice.

2025-03-20 | E-MTAB-14917 | biostudies-arrayexpress

Absence of microglia promotes diverse pathologies andearly lethality in Alzheimer's disease mice

Project description:Microglia are strongly implicated in the development and progression of Alzheimer’s disease (AD), yet the precise mechanisms underlying their effects on neuropathology remain unclear. To further define the influence of microglia on AD neuropathology, we generated a novel mouse model of AD that genetically lack microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid plaques to cerebral amyloid angiopathy (CAA) that is further accompanied by transcriptional changes within multiple cell types, a dramatic induction of brain calcification and cerebral hemorrhages, and premature lethality. Importantly, adult microglia replacement fully rescues these comorbidities, supporting novel roles for microglia in maintaining vascular function and preventing brain calcification. We further examined the clinical implications of these findings in human tissue and hiPSC-derived microglia, finding evidence that calcification is inversely related to plaque pathology and that microglial interactions with calcifications are altered by genetic AD risk factors.

2021-11-24 | GSE189033 | GEO

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