Amyloid Accumulation Drives Proteome-wide Alterations in Mouse Models of Alzheimer’s Disease-like Pathology
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Abstract
Amyloid beta (Aβ) peptides impair multiple cellular pathways and play a causative role in Alzheimer's disease (AD) pathology, but how the brain proteome is remodeled by this process is unknown. To identify protein networks associated with AD-like pathology, we performed global quantitative proteomic analysis in three mouse models at young and old ages. Our analysis revealed a robust increase in Apolipoprotein E (ApoE) levels in nearly all brain regions with increased Aβ levels. Taken together with prior findings on ApoE driving Aβ accumulation, this analysis points to a pathological dysregulation of the ApoE-Aβ axis. We also found dysregulation of protein networks involved in excitatory synaptic transmission. Analysis of the AMPA receptor (AMPAR) complex revealed specific loss of TARPγ-2, a key AMPAR-trafficking protein. Expression of TARPγ-2 in hAPP transgenic mice restored AMPA currents. This proteomic database represents a resource for the identification of protein alterations responsible for AD.
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The WAVE1 gene has been suggested as an AD-associated hub gene from studies of AD mouse models or human AD brains.
“The WAVE1 gene has also been suggested as an AD-associated hub gene from studies of AD mouse models148 or human AD brains149.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [148]
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The WAVE complex in developmental and adulthood brain disorders
Kim, H.-G., Berdasco, C., Nairn, A. C., & Kim, Y. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01386-w · Cited by 8 · see citing works
- Authors
- Savas, J. N., Wang, Y.-Z., DeNardo, L. A., Martinez-Bartolome, S., McClatchy, D. B., Hark, T. J., Shanks, N. F., Cozzolino, K. A., Lavallée-Adam, M., Smukowski, S. N., Park, S. K., Kelly, J. W., Koo, E. H., Nakagawa, T., Masliah, E., Ghosh, A., & Yates, J. R.
- Affiliations
- Northwestern University (US)
- University of California San Diego (US)
- Scripps Research Institute (US)
- Corresponding author
- Savas, Jeffrey N.
- Yates, John R.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 21
- Issue
- 9
- Pages
- 2614-2627
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5726791
- OpenAlex
- W2625912305
- Cited by
- 66
- References
- 13
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 6 · 2023: 6 · 2022: 3 · 2021: 10 · 2020: 13 · 2019: 11 · 2018: 5
- FWCI
- 5.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- NIH (F32AG039127, R00DC013805, R01MH067880, P41GM103533, P30CA060553)
- Fonds de Recherche du Québec—Nature et Technologies fellowship
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Alzheimer's disease, amyloid-beta, apolipoprotein E, brain proteome, AMPA receptors, excitatory synaptic transmission, protein networks
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Brain, Female, Mice, Inbred C57BL, Mass Spectrometry, Calcium Channels, Amyloid beta-Peptides, Computational Biology, Proteome, Mice
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