Molecular Signatures Underlying Selective Regional Vulnerability to Alzheimer's Disease
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE84422 | GEO | 2016/08/19
SECONDARY ACCESSION(S): PRJNA329139
REPOSITORIES: GEO
Similar Datasets
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. 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.
2016-08-19 | E-GEOD-84422 | biostudies-arrayexpress
Project description:Alzheimer’s disease (AD) and Lewy body dementia (LBD) are two different forms of dementia but their pathology may involve the same cortical areas with overlapping cognitive manifestation. Dementia cases within the same family share a common genetic background. Nonetheless, the clinical phenotype may be different due to the different underlying molecular processes that come-up apart from genetics, causing diverse neurodegeneration. Through neuropathological, genetic and transcriptomic comparison of four different brain areas (substantia nigra, hippocampus, parietal lobe and basal ganglia), we defined commonalities and differences in the pathological processes of dementia in two kindred cases, a mother and a son, who developed a classical AD and an aggressive form of AD/LBD respectively. Genetic analysis did not reveal any pathogenic variants in the principal AD/LBD-causative genes. RNA sequencing highlighted high transcriptional dysregulation within the substantia nigra in LBD pathology, while AD underwent lower degree of transcriptional dysregulation, with the parietal lobe being the most involved brain area. Conversely, hippocampus (the most degenerated area) and basal ganglia (lacking specific lesions) expressed the lowest level of dysregulation. Our data suggest that there is a link between the transcriptional dysregulation and the amount of tissue damage accumulated across time, assessed through neuropathology. Moreover, we highlight that the molecular bases of AD and LBD follow very different pathways, which underlie their neuropathological signatures. Indeed, the transcriptome profiling through RNA sequencing may be an important tool in flanking the neuropathological analysis for a deeper understanding of AD and LBD pathogenesis.
2022-08-03 | GSE193438 | GEO
Project description:Brain tissue of 3 patients with Alzheimer's disease (AD) and 3 healthy controls dying without any history of neurological or psychiatric illness was used. The diagnosis of AD was made on the basis of both clinical and neuropathological evidence according to the criteria of the International Working Group (IWG) for New Research Criteria for the diagnosis of AD in the revision of 2014 (IWG-2),16 the NIA-AA diagnostic criteria in the revision of 201117 and the NIA-AA guidelines for the neuropathological assessment of AD. Only cases with typical AD according to IWG-2 criteria were included. Transcriptome-wide expression of AD and healthy control samples was assessed with Affymetrix Human Whole Genome Tiling Array 1.0 Set.
2022-01-19 | GSE138214 | GEO
Project description:Aging is often characterized by a progressive loss of cognitive abilities due to the onset of different forms of dementia. Among these, Alzheimer’s Disease (AD) and dementia with Lewy bodies (LBD) are the most widespread ones. However, little is known about the common aspects between these conditions and how these aspects can be linked to aging itself. With this work, we aim to identify a molecular fil rouge that could link aging and different dementias in order to possibly highlight strategic targets for novel therapeutical approaches. A whole transcriptome analysis and a Gene Set Enrichment Analysis (GSEA) have been carried out on brain samples from hippocampus (HI), temporal and parietal cortex (TC, PC), cingulate cortex (CG), and substantia nigra (SN) from the Abbiategrasso Brain Bank (ABB) of subjects with a neuropathological diagnosis of AD and LBD (6 per pathology) and 3 age-matched controls with no dementia (CTRLs). Clinical and neuropsychological profile were obtained through serial evaluations, made at the baseline and in the following years. According to the ABB protocol, the neuropathological diagnosis was based on a complete histological characterization, including all the main proteinopathies and vascular scoring. Transcriptomic results showed some major differences in the number of differentially expressed genes (DEGs) between the two pathologies and in particular that AD brains gene expression is more affected compared to LBD’s one (DEGsAD=3156; DEGsLBD=278). Furthermore, the GSEA showed that in AD it is possible to cluster the analysed regions by biological processes (HI and TC: DEGs primarily related to synaptic transmission; PC, CG and SN: DEGs primarily related to proper protein folding and inflammation) while in LBD there is only a strong and peculiar involvement of SN (DEGs primarily related to proper protein folding and inflammation) and PC (DEGs primarily related to myelination and glial system activation). AD and LBD are different forms of dementia characterized by a definite time and severity-related pattern. Therefore, it is possible to draw a molecular map of pathology spreading in the brain that could unveil unexplored roads and possible shortcuts leading to a better understanding of AD and LBD pathogenesis. This could help to discover novel biological targets in order to develop effective and well-timed therapeutical approaches.
2024-10-24 | GSE280268 | GEO
Project description:Alzheimer's disease (AD) is the most common type of dementia. Extracellular amyloid β (Aβ) plaques and intracellular Tau-containing neurofibrillary tangles are major AD lesions that identify Alzheimer’s pathology and to neuronal loss. However, given that these structures are also seen in cognitively normal persons (healthy controls, HC) and in persons who have mild cognitive impairment (MCI), extensive efforts have been undertaken to identify other diagnostic or prognostic indicators. Here, we characterized the RNA contents of extracellular vesicles (EVs) in the plasma of age-matched individuals who are healthy or have MCI or AD. Using RNA sequencing analysis, we found that mitochondrial (mt)RNAs, including MT-ND1 through MT-ND6 and other protein-coding and noncoding mtRNAs, were strikingly elevated in MCI- and AD-associated plasma EVs compared with healthy control EVs. In cultured cells derived from astrocytes, microglia, and neurons, exposure to the toxic conditions in the AD environment (Aβ fibers and H2O2), EVs contained mitochondrial structures (as detected by electron microscopy) as well as mitochondrial RNAs. We propose that in the MCI and AD brain environment, toxicity causing mitochondrial damage results in the packaging of mitochondrial components for export in EVs, and further propose that mitochondrial RNAs in plasma EVs are robust diagnostic and prognostic markers in AD.
2020-12-15 | GSE153881 | GEO
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
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
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.
2014-08-17 | GSE59685 | GEO
Project description:Alzheimer’s disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To identify and characterize selectively vulnerable neuronal populations, we used single-nucleus RNA sequencing to profile the caudal entorhinal cortex and the superior frontal gyrus – brain regions where neurofibrillary inclusions and neuronal loss occur early and late in AD, respectively – from individuals spanning the neuropathological progression of AD. We identified RORB as a marker of selectively vulnerable excitatory neurons in the entorhinal cortex, and subsequently validated their depletion and selective susceptibility to neurofibrillary inclusions during disease progression using quantitative neuropathological methods. We also discovered an astrocyte subpopulation, likely representing reactive astrocytes, characterized by decreased expression of genes involved in homeostatic functions. Our characterization of selectively vulnerable neurons in AD paves the way for future mechanistic studies of selective vulnerability and potential therapeutic strategies for enhancing neuronal resilience. The brain tissue used in this study were sourced from the Biobank for Aging Studies (LIM-22) in the Department of Pathology at the University of Sao Paulo, as well as from the Neurodegenerative Diseases Brain Bank in the Memory and Aging Center at the University of California, San Francisco. Detailed neuropathological, clinical and genetic data are available under request. Please contact gerolab@gmail.com and lea.grinberg@ucsf.edu.
2020-04-05 | GSE147528 | GEO
Project description:MicroRNAs (miRNAs) are small (20-22 nucleotides) regulatory non-coding RNAs that strongly influence gene expression. Most prior studies addressing the role of miRNAs in neurodegenerative diseases (NDs) have focused on individual controls (n = 2), AD (n = 5), dementia with Lewy bodies (n = 4), hippocampal sclerosis of aging (n = 4), and frontotemporal lobar dementia (FTLD) (n = 5) cases, together accounting for the most prevalent ND subtypes. All cases had short postmortem intervals, relatively high-quality RNA, and state-of-the-art neuropathological diagnoses. The resulting data (over 113 million reads in total, averaging 5.6 million reads per sample) and secondary expression analyses constitute an unprecedented look into the human cerebral cortical miRNome at single nucleotide resolution. While we find no apparent changes in isomiR or miRNA editing patterns in correlation with ND pathology, our results validate and extend previous miRNA profiling studies with regard to quantitative changes in NDs. In agreement with this idea, we provide independent cohort validation for changes in miR-132 expression levels in AD (n = 8) and FTLD (n = 14) cases when compared to controls (n = 8). The identification of common and ND-specific putative novel brain miRNAs and/or short-hairpin molecules is also presented. The challenge now is to better understand the impact of these and other alterations on neuronal gene expression networks and neuropathologies. Using RNA deep sequencing, we sought to analyze in detail the small RNAs (including miRNAs) in the temporal neocortex gray matter from non-demented controls (n = 2), AD (n = 5), dementia with Lewy bodies (n = 4), hippocampal sclerosis of aging (n = 4), and frontotemporal lobar dementia (FTLD) (n = 5) cases, together accounting for the most prevalent ND subtypes.
2013-04-18 | E-GEOD-46131 | biostudies-arrayexpress