Temporal and Sex-Linked Protein Expression Dynamics in a Familial Model of Alzheimer's Disease.
5XFAD
Alzheimer's Disease
Pathway analysis
Proteome
Sex differences
Temporal dynamics
Journal
Molecular & cellular proteomics : MCP
ISSN: 1535-9484
Titre abrégé: Mol Cell Proteomics
Pays: United States
ID NLM: 101125647
Informations de publication
Date de publication:
09 2022
09 2022
Historique:
received:
14
12
2021
revised:
27
07
2022
accepted:
03
08
2022
pubmed:
10
8
2022
medline:
28
9
2022
entrez:
9
8
2022
Statut:
ppublish
Résumé
Mouse models of Alzheimer's disease (AD) show progression through stages reflective of human pathology. Proteomics identification of temporal and sex-linked factors driving AD-related pathways can be used to dissect initiating and propagating events of AD stages to develop biomarkers or design interventions. In the present study, we conducted label-free proteome measurements of mouse hippocampus tissue with variables of time (3, 6, and 9 months), genetic background (5XFAD versus WT), and sex (equal males and females). These time points are associated with well-defined phenotypes with respect to the following: Aβ42 plaque deposition, memory deficits, and neuronal loss, allowing correlation of proteome-based molecular signatures with the mouse model stages. Our data show 5XFAD mice exhibit increases in known human AD biomarkers as amyloid-beta peptide, APOE, GFAP, and ITM2B are upregulated across all time points/stages. At the same time, 23 proteins are here newly associated with Alzheimer's pathology as they are also dysregulated in 5XFAD mice. At a pathways level, the 5XFAD-specific upregulated proteins are significantly enriched for DNA damage and stress-induced senescence at 3-month only, while at 6-month, the AD-specific proteome signature is altered and significantly enriched for membrane trafficking and vesicle-mediated transport protein annotations. By 9-month, AD-specific dysregulation is also characterized by significant neuroinflammation with innate immune system, platelet activation, and hyper-reactive astrocyte-related enrichments. Aside from these temporal changes, analysis of sex-linked differences in proteome signatures uncovered novel sex and AD-associated proteins. Pathway analysis revealed sex-linked differences in the 5XFAD model to be involved in the regulation of well-known human AD-related processes of amyloid fibril formation, wound healing, lysosome biogenesis, and DNA damage. Verification of the discovery results by Western blot and parallel reaction monitoring confirm the fundamental conclusions of the study and poise the 5XFAD model for further use as a molecular tool for understanding AD.
Identifiants
pubmed: 35944844
pii: S1535-9476(22)00088-3
doi: 10.1016/j.mcpro.2022.100280
pmc: PMC9483563
pii:
doi:
Substances chimiques
Amyloid
0
Amyloid beta-Peptides
0
Apolipoproteins E
0
Biomarkers
0
Proteome
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
100280Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM117208
Pays : United States
Organisme : NIH HHS
ID : S10 OD026882
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG074346
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG065240
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS115903
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG076051
Pays : United States
Organisme : NIH HHS
ID : S10 OD028614
Pays : United States
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest The authors declare no competing interests.
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