Temporal dynamics of hippocampal protein expression in a familial model of Alzheimer's Disease
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Exploris 480
ORGANISM(S): Mus Musculus (ncbitaxon:10090)
SUBMITTER: 
Mark R. Chance
PROVIDER: MSV000088507 | MassIVE | Fri Dec 03 15:25:00 GMT 2021
REPOSITORIES: MassIVE
Similar Datasets
Project description:Mouse models of Alzheimer’s Disease (AD), which show progression through various AD stages reflective of human pathology, like 5XFAD, are well established tools for uncovering novel AD related pathways. In addition, they permit temporal examination of the intermingling of AD related pathways and can be used to potentially dissect initiating and propagating events in AD, which are critical for developing biomarkers or designing interventions in early stages of the disease. The present research offers a robust and exhaustive tandem MS examination of a familial AD mice model with a design including variables of: time (three, six, and nine months), genetic background (5XFAD vs. WT), and sex (equal males and females).
2022-09-16 | PXD030161 | Pride
Project description:Protein from astrocytes (glial fibrillary acidic protein-positive cells), neurons (beta-III tubulin-positive cells), and unsorted (cell suspension without any enrichment based on astrocyte or neuron markers) from human, post-mortem Alzheimer's disease (AD) and aged-matched non-symptomatic (NS) prefrontal cortex brain samples.
2019-05-06 | MSV000083747 | MassIVE
Project description:Loss-of-function mutations in TREM2 (triggering receptor expressed on myeloid cells 2) strongly increase Alzheimer’s disease (AD) risk. Preclinical models using Trem2 deletion or overexpression have revealed a protective Trem2 function related to β-amyloid accumulation, a process that is most prominent during the pre-diagnosis stages of AD. The role of TREM2 in later AD stages characterized by tau-mediated neurodegeneration is less clear. To understand Trem2 function in the context of both β-amyloid and tau pathologies, we examined Trem2-deficient mice expressing mutant tau alone (pR5-183 model) or in the TauPS2APP model, in which β-amyloid pathology exacerbates tau pathology and neurodegeneration. Single-cell RNA-sequencing in these models revealed robust disease-associated microglia (DAM) activation in TauPS2APP mice that was both amyloid-dependent and Trem2-dependent. In the presence of β-amyloid pathology, Trem2 deletion further exacerbated tau accumulation and spreading and promoted brain atrophy. Without β-amyloid pathology, Trem2 deletion did not affect these processes. Therefore, TREM2 may slow AD progression and reduce tau-driven neurodegeneration by restricting the degree to which β-amyloid facilitates the spreading of pathogenic tau
2021-02-24 | GSE153895 | GEO
Project description:Alzheimer’s disease (AD) is an unremitting neurodegenerative disorder characterized by cerebral amyloid-β (Aβ) accumulation and gradual decline in cognitive function. Changes in brain energy metabolism arise in the preclinical phase of AD, suggesting an important metabolic component of early AD pathology. Neurons and astrocytes function in close metabolic collaboration, which is essential for the recycling of neurotransmitters in the synapse. However, how this metabolic interplay may be affected during the early stages of AD development has not been sufficiently investigated. Here, we provide an integrative analysis of cellular metabolism during the early stages of Aβ accumulation in the cerebral cortex and hippocampus of the 5xFAD mouse model of AD. Our electrophysiological examination revealed an increase in spontaneous excitatory signaling in hippocampal brain slices of 5xFAD mice. This hyperactive neuronal phenotype coincided with decreased hippocampal TCA cycle metabolism mapped by stable 13C isotope tracing. Particularly, reduced astrocyte TCA cycle activity led to decreased glutamine synthesis, in turn hampering neuronal GABA synthesis in the 5xFAD hippocampus. In contrast, cerebral cortical slices of 5xFAD mice displayed an elevated capacity for oxidative glucose metabolism suggesting a metabolic compensation. When we explored the brain proteome and metabolome of the 5xFAD mice, we found limited changes, supporting that the functional metabolic disturbances between neurons and astrocytes are early events in AD pathology. In addition, we show that synaptic mitochondrial and glycolytic function was impaired selectively in the 5xFAD hippocampus, whereas non-synaptic mitochondrial function was maintained. These findings were supported by ultrastructural analyses demonstrating disruptions in mitochondrial morphology, particularly in the 5xFAD hippocampus. Collectively, our study reveals complex region and cell specific metabolic adaptations, in the early stages of amyloid pathology, which may be fundamental for the progressing synaptic dysfunction in AD.
2021-11-09 | PXD025240 | Pride
Project description:Steckmann2012 - Amyloid beta-protein
fibrillogenesis (kinetics of secondary structure conversion)
This model is described in the article:
Kinetics of peptide
secondary structure conversion during amyloid ?-protein
fibrillogenesis.
Steckmann T, Awan Z, Gerstman BS,
Chapagain PP.
J. Theor. Biol. 2012 May; 301:
95-102
Abstract:
Amyloid fibrils are a common component in many debilitating
human neurological diseases such as Alzheimer's (AD),
Parkinson's, and Creutzfeldt-Jakob, and in animal diseases such
as BSE. The role of fibrillar ?? proteins in AD has stimulated
interest in the kinetics of ?? fibril formation. Kinetic models
that include reaction pathways and rate parameters for the
various stages of the process can be helpful towards
understanding the dynamics on a molecular level. Based upon
experimental data, we have developed a mathematical model for
the reaction pathways and determined rate parameters for
peptide secondary structural conversion and aggregation during
the entire fibrillogenesis process from random coil to mature
fibrils, including the molecular species that accelerate the
conversions. The model and the rate parameters include
different molecular structural stages in the nucleation and
polymerization processes and the numerical solutions yield
graphs of concentrations of different molecular species versus
time that are in close agreement with experimental results. The
model also allows for the calculation of the time-dependent
increase in aggregate size. The calculated results agree well
with experimental results, and allow differences in
experimental conditions to be included in the calculations. The
specific steps of the model and the rate constants that are
determined by fitting to experimental data provide insight on
the molecular species involved in the fibril formation
process.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000533.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2014-07-30 | BIOMD0000000533 | BioModels
Project description:Background: Diabetes mellitus (DM) is a recognized risk factor for dementias, including AD, increasing its odds by two-fold. Because DM is potentially modifiable risk factor, a greater understanding of the mechanisms linking DM to the clinical expression of AD may provide insights into much needed dementia therapeutics. Epigenetics offers a novel approach, and previously under-investigated 5-hydroxymethylcytosines (5hmC) is now emerging as a promising measure to investigate in diabetes related conditions. Methods: Using 5hmC-Seal, a highly sensitive chemical labeling technique developed by our team, we performed genome-wide profiling of 5hmC in circulating cell-free DNA (cfDNA) and prefrontal cortex tissue from 80 individuals across four groups: AD, DM, DM and AD (AD+DM), and non-AD/non-DM controls. We used differential analysis and machine-learning to explore whether 5hmC and biological pathways might be implicated in DM-associated AD under a balanced design. Results: We uncovered distinct 5hmC genome-wide signatures and biological pathways associated with AD or AD+DM compared to non-AD/non-DM controls or DM alone. We further demonstrated potential diagnostic value of 5hmC profiling in circulating cfDNA through feature selection based on machine learning. Conclusions: Genome-wide 5hmC profiling uncovered genomic features and biological pathways linking DM to DM-associated AD. Our findings also demonstrate the potential of utilizing 5hmC in circulating cfDNA as diagnostic biomarkers or disease monitoring tools, with the ultimate goal of preventing or ameliorating DM-associated AD dementia and improving clinical outcomes.
2023-05-16 | GSE203337 | GEO
Project description:Core spliceosome and related RNA-binding proteins aggregate in Alzheimer’s disease (AD) brain even in early asymptomatic stages (AsymAD) of disease. To assess the specificity of RNA-binding protein aggregation in AD, we developed a targeted mass spectrometry approach to quantify broad classes of RNA-binding proteins with other pathological proteins including Tau and amyloid beta (Aβ) in detergent insoluble fractions from AD brain and that of other dementias. In total, we quantified 870 peptides from 385 detergent-insoluble RNA-binding proteins across 44 cortical tissues including controls, AsymAD, AD, and Parkinson’s Disease (PD). Relative levels of specific insoluble RNA-binding proteins across different disease groups correlated with accumulation of Aβ and Tau aggregates. RNA-binding proteins, including splicing factors with homology to the basic-acidic dipeptide repeats of U1-70K, preferentially aggregated in AsymAD and AD. In contrast, PD brain aggregates were relatively depleted of many RNA-binding proteins compared to AsymAD and AD groups. Correlation network analyses resolved 29 distinct modules of co-aggregating proteins including modules linked to spliceosome assembly, nuclear speckles and RNA splicing. Modules related to spliceosome assembly and nuclear speckles progressively increased in insolubility across progressive AD stages, whereas the RNA splicing module was decreased specifically in PD. Collectively, this work identifies classes of RNA-binding proteins that distinctly co-aggregate in detergent-insoluble fractions across neurodegenerative diseases.
2021-03-17 | PXD022144 | Pride
Project description:Alzheimer’s Disease (AD) is the most common cause of dementia in the elderly population without a cure or early diagnostics currently available. Despite the demonstrated ability of extracellular vesicles (EVs) to spread tau and Aβ pathology in AD models and their potential utility as a diagnostic and treatment-monitoring tool, our knowledge of human brain EV subpopulations, their molecular composition and roles in disease progression is very limited. Genome-wide association studies linked multiple AD genetic risk factors to microglia-specific pathways suggesting a potential role of microglia-derived EVs in AD progression. Here we are presenting a method for isolation of microglial CD11b-positive small EVs from cryopreserved human brain tissue and multi-omics analysis of the EVs from the parietal cortex of 4 late-stage AD (Braak V-VI) and 3 age-matched normal/low pathology (NL) cases. We identified a total of 1000 proteins by quantitative proteomics, analyzed 594 individual lipid species by targeted lipidomics, and 105 miRNAs using a NanoString miRNA expression panel. We found significant reduction in abundance of homeostatic microglia markers, P2RY12 and TMEM119, and increased levels of disease associated microglia markers, FTH1 and TREM2, in microglial EVs from AD brain compared to NL cases. Protein tau abundance was also significantly higher in AD brain-derived microglial EVs. These changes were accompanied by upregulation of synaptic and neuron-specific proteins in the AD group. Levels of free-cholesterol were elevated in microglial EVs from AD brain. Lipidomic analysis also revealed a pro-inflammatory lipid profile, endolysosomal dysfunction and significant AD-associated decrease in levels of docosahexaenoic acid (DHA)-containing polyunsaturated lipids of different classes, suggesting a potential defect in acyl-chain remodeling. Several immune pathways and senescence were among the top pathways controlled by 4 miRNAs significantly upregulated in the AD group. Our data suggest that loss of the homeostatic microglia signature in late AD stages may accompany endolysosomal impairment and release of undigested neuronal and myelin debris, including tau, through extracellular vesicles. These data validate a method of isolation of small cell-type specific EVs from human brain tissue, suggests new potential EV-associated markers and disease-related pathways, and provides a framework for future large-scale multi-omics study.
2021-11-25 | PXD028898 | Pride
Project description:In this study, we construct network models by integrating multi-omics data in ROSMAP and MAYO cohort in AMP-AD consortium and infer 19 potential key drivers for Alzheimer’s Disease and related dementia (ADRD). To validate these 19 targets in modulating AD-related pathology (Amyloid-beta and phosphorylated-Tau) and investigating the biological functions and pathways they regulate, we performed RNAi-based knockdown of 19 targets inferred by computational systems biology model in human iPSC-derived neurons (iNs) and measured gene expression profile for each knockdown by RNAseq.
2023-04-01 | GSE228156 | GEO
Project description:Alzheimer's disease (AD) is the most prevalent form of dementia and the number of AD patients is expected to increase as human life expectancy improves. The deposition of β-amyloid protein (Aβ) in the extracellular matrix and neurofibrillary tangles intracellularly are pathologic hallmarks. Since the precise pathophysiology of AD has not been clearly elucidated yet, effective treatment is not available. Thus the development of valid AD biomarkers is imperative for early diagnosis and for monitoring disease progression and therapeutic responses.
2022-04-01 | PXD010560 | Pride