Probing protein structural changes in Alzheimer's disease via quantitative crosslinking mass spectrometry
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Fusion Lumos
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Lingjun Li
PROVIDER: MSV000094259 | MassIVE | Thu Mar 07 11:42:00 GMT 2024
SECONDARY ACCESSION(S): PXD050457
REPOSITORIES: MassIVE
Similar Datasets
Project description:This study investigates stress's impact on Alzheimer's disease (AD) using male APP/PS1 transgenic mice. Negative stressors (chronic social defeat, restraint) and positive hedonia (environmental enrichment, EE) were applied. Stress worsens AD pathology, while EE slows progression. Brain RNA-seq reveals IL-6 and IL-10 as key stress-related AD regulators. Flow cytometry shows CD8+/CD4+ T cell ratio shifts in response to SE and EE. SE increases CD8+/CD4+ ratio, opposite in EE. Depletion and enrichment of CD8+ T cells both accelerate AD, indicating immune intervention's negative impact. Stress management and balanced immunity may aid AD therapy, highlighting novel potential treatment.
2023-12-15 | GSE244131 | GEO
Project description:We investigated spatiotemporal molecular patterns related to AD pathophsiology using spatially resolved transcriptome of the AD mouse model. The late change of gray matters of AD was commonly related to neuroinflammation, while the early change in the white matter of AD represented neuronal projection and ensheathment of axons before the amyloid plaques accumulation. Disease-associated microglia and astrocyte signatures were spatially differently enriched. Our results provide a key spatiotemporally heterogeneous molecular change particularly related to inflammation in AD.
2024-01-10 | GSE174321 | GEO
Project description:Along with the two hallmark pathologies—intracellular neurofibrillary tangles (NFTs) and extracellular amyloid plaques—transcriptional studies suggest that Alzheimer's disease (AD) results from dysfunction of many cellular pathways including synaptic transmission, cytoskeletal dynamics, and apoptosis. While these studies consistently point to the same pathways involved in AD, there is no consensus on which genes in each pathway are disease-relevant, much less on whether these genes play causative roles or are downstream effects of disease progression. To address these issues, we have performed a large-scale transcriptional analysis in brain of individuals with advanced AD and non-demented controls, focusing specifically on CA1 and the relatively less affected CA3. For comparisons between regions and across disease status, we find consistency in both pathway enrichment as well as specific differentially expressed genes across several studies. Furthermore, genes that show decreased expression with AD progression also tend to show enrichment in CA3 (and vice versa), suggesting that transcription levels in a region may reflect that region's vulnerability to disease. In particular, we find several strong candidate vulnerability (ABCA1, MT1H, PDK4, RHOBTB3) and protection (FAM13A1, LINGO2, UNC13C) genes based on expression patterns. We have also applied weighted gene coexpression network analysis (WGCNA) to explore the pathophysiology of AD from a systems perspective, finding modules for major cell types, which each show distinct disease-relevant expression patterns. In particular, a microglial module shows increased expression in the brain of non-demented controls harboring early NFT pathology, suggesting that microglial activation is an early event in AD progression. Total RNA obtained from 60um sections of frozen human hippocampus was collected using scalpel dissection. Control and AD brains were matched for all non-disease characteristics as closely as possible. CA1 and CA3 dissections for a given individual were taken from the same section. Several region- and disease-related comparisons were performed.
2013-06-07 | E-GEOD-29378 | biostudies-arrayexpress
Project description:Late-onset Alzheimer’s disease (LOAD) is the most common form of AD. However, modeling sporadic LOAD, without clear genetic predispositions, to capture hallmark neuronal pathologies such as extracellular amyloid-β (Aβ) plaque deposition, intracellular tau tangles, and neuronal loss, remains an unmet need. Here, we demonstrate that neurons generated by microRNA-based direct reprogramming of fibroblasts from patients affected by autosomal dominant AD (ADAD) and LOAD in a three-dimensional (3D) environment, effectively recapitulate key neuropathological features of AD without additional cellular or genetic insults. These LOAD neurons exhibit Aβ-dependent neurodegeneration, as treatment with β- or γ-secretase inhibitors before (but not subsequent to) Aβ deposit formation mitigated neuronal death. Moreover, inhibiting age-associated retrotransposable elements (RTEs) in LOAD neurons reduced both Ab deposition and neurodegeneration. Our study underscores the efficacy of modeling late-onset neuropathology of LOAD through high-efficiency microRNA-based neuronal reprogramming.
2024-08-05 | GSE252932 | GEO
Project description:To identify molecular pathological alterations in AD brains, we performed interspecies comparative microarray analyses using RNAs prepared from postmortem human brain tissues donated for the Hisayama study and hippocampal RNAs from the triple-transgenic mouse model of AD (3xTg-AD) Three-way ANOVA of microarray data from frontal cortex, temporal cortex and hippocampus with presence/absence of AD and vascular dementia, and sex, as factors revealed that the gene expression profile is most significantly altered in the hippocampi of AD brains. Comparative analyses of the brains of AD patients and a mouse model of AD showed that genes involved in non-insulin dependent DM and obesity were significantly altered in both, as were genes related to psychiatric disorders and AlzheimerM-bM-^@M-^Ys disease. 3xTg-AD-H mice harboring a homozygous Psen1M146V mutation and homozygous mutant transgenes for APPSwe and tauP301L, 3xTg-AD-h mice harboring hemizygous APPSwe and tauP301L transgenes with a homozygous Psen1M146V mutation, and non-transgenic control mice (non-Tg) were used in this study, (male, n=3 for each group). RNA samples prepared from hippocampi were subjected to microarray analysis using the Affymetrix Mouse Gene 1.0 ST platform (GPL6246).
2013-04-17 | E-GEOD-36981 | biostudies-arrayexpress
Project description:The aim of the present project is to detect biochemical alterations that can pinpoint specific pathogenic processes at early phases of AD, evaluated in the cerebrospinal fluid, that more closely reflect the pathogenic processes in the brain, and independently of whether an amyloid response was triggered.
2024-05-24 | PXD039563 | Pride
Project description:Due to its high pharmaceutical relevance, α-synuclein is one of the best studied intrinsically disordered proteins to date. Its structural plasticity reaches from α-helical when bound to membranes through disordered in solution to β-sheet when forming amyloid fibrils. Recently the possible toxicity of membrane bound α-synuclein oligomers has elicited increased interest in the understanding of its membrane bound state. Both the high structural variability in the bound state and the requirement of membranes to elicit structural conversion of α-synuclein into is oligomeric membrane bound state have impeded the determination of a high-resolution oligomeric membrane-bound structure. The use of chemical crosslinking mass spectrometry (XL-MS) in this context leads to a very large set of peptide spectrum matches (PSMs), which do not permit the elucidation of a single, well defined structure based on XL-MS alone. The pattern of PSMs obtained does, however, represent possible links within the ensemble of membrane bound α-synuclein states. Here, we use fully 15N isotopically labeled α-synuclein in 1:1 mixtures with the natural abundance (14N) protein in order to allow distinction between intermolecular and intramolecular crosslinks in α-synuclein oligomers. Information obtained on the main crosslinking regions as well as changes in the observed PSM patterns is then used in conjunction with data obtained from nuclear magnetic resonance (NMR) measurements to develop high-resolution structural models of α-synuclein. We expect that the approach taken here will also prove useful in other highly flexible oligomeric systems.
2023-04-07 | PXD027349 | Pride
Project description:Late-onset Alzheimer’s disease (LOAD) is the most common form of AD. However, modeling sporadic LOAD, without clear genetic predispositions, to capture hallmark neuronal pathologies such as extracellular amyloid-β (Aβ) plaque deposition, intracellular tau tangles, and neuronal loss, remains an unmet need. Here, we demonstrate that neurons generated by microRNA-based direct reprogramming of fibroblasts from patients affected by autosomal dominant AD (ADAD) and LOAD in a three-dimensional (3D) environment, effectively recapitulate key neuropathological features of AD without additional cellular or genetic insults. These LOAD neurons exhibit Aβ-dependent neurodegeneration, as treatment with β- or γ-secretase inhibitors before (but not subsequent to) Aβ deposit formation mitigated neuronal death. Moreover, inhibiting age-associated retrotransposable elements (RTEs) in LOAD neurons reduced both Ab deposition and neurodegeneration. Our study underscores the efficacy of modeling late-onset neuropathology of LOAD through high-efficiency microRNA-based neuronal reprogramming.
2024-08-05 | GSE253174 | GEO
Project description:Late-onset Alzheimer’s disease (LOAD) is the most common form of AD. However, modeling sporadic LOAD, without clear genetic predispositions, to capture hallmark neuronal pathologies such as extracellular amyloid-β (Aβ) plaque deposition, intracellular tau tangles, and neuronal loss, remains an unmet need. Here, we demonstrate that neurons generated by microRNA-based direct reprogramming of fibroblasts from patients affected by autosomal dominant AD (ADAD) and LOAD in a three-dimensional (3D) environment, effectively recapitulate key neuropathological features of AD without additional cellular or genetic insults. These LOAD neurons exhibit Aβ-dependent neurodegeneration, as treatment with β- or γ-secretase inhibitors before (but not subsequent to) Aβ deposit formation mitigated neuronal death. Moreover, inhibiting age-associated retrotransposable elements (RTEs) in LOAD neurons reduced both Ab deposition and neurodegeneration. Our study underscores the efficacy of modeling late-onset neuropathology of LOAD through high-efficiency microRNA-based neuronal reprogramming.
2024-08-05 | GSE267613 | GEO
Project description:This dataset contains microarray data from normal controls (aged 20-99 yrs) and Alzheimer's disease cases, from 4 brain regions: hippocampus, entorhinal cortex, superior frontal cortex, post-central gyrus. Changes in expression of synaptic and immune related genes were analyzed, investigating age-related changes and AD-related changes, and region-specific patterns of change. These AD cases were processed simultaneously with the control cases (young and aged) included in GSE11882 (GSE11882 dataset contains data exclusively from normal control brains).
2014-04-21 | GSE48350 | GEO