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Cited by 37Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchAdvanced Proteomics Techniques and Applications

Brain proteomic analysis implicates actin filament processes and injury response in resilience to Alzheimer’s disease

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Huang, Zhi, Merrihew, Gennifer E., Larson, Eric B., Park, Jea, Plubell, Deanna, Fox, Edward J., Montine, Kathleen S., Latimer, Caitlin S. +4 more·2023·Nature Communications
DOI 10.1038/s41467-023-38376-xPMC PMC10182086
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Abstract

Resilience to Alzheimer’s disease is an uncommon combination of high disease burden without dementia that offers valuable insights into limiting clinical impact. Here we assessed 43 research participants meeting stringent criteria, 11 healthy controls, 12 resilience to Alzheimer’s disease and 20 Alzheimer’s disease with dementia and analyzed matched isocortical regions, hippocampus, and caudate nucleus by mass spectrometry-based proteomics. Of 7115 differentially expressed soluble proteins, lower isocortical and hippocampal soluble Aβ levels is a significant feature of resilience when compared to healthy control and Alzheimer’s disease dementia groups. Protein co-expression analysis reveals 181 densely-interacting proteins significantly associated with resilience that were enriched for actin filament-based processes, cellular detoxification, and wound healing in isocortex and hippocampus, further supported by four validation cohorts. Our results suggest that lowering soluble Aβ concentration may suppress severe cognitive impairment along the Alzheimer’s disease continuum. The molecular basis of resilience likely holds important therapeutic insights.

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  • Actin network proteins in neurons play a crucial role in conferring resilience to AD.

    “Interestingly, a recent study that used mass spectrometry-based proteomics has pointed out the crucial role of actin network proteins in neurons to confer resilience to AD [39].”

    From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [39]

    The Results and Discussion associate actin filament processes with resilience to Alzheimer’s disease and relate actin dynamics to dendrite and synapse remodeling. But the Discussion says future studies must determine whether modulating these processes is necessary for resilience; the study does not establish that neuronal actin proteins confer it or play a crucial causal role. Page numbers are unavailable in our copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • ARP2, CAP1, and CFL1 are proteins related to engulfment processes through actin-based motility mechanisms, and were recently associated with AD resilience according to protein coexpression analysis.

    “In this context, ARP2, CAP1, and CFL1 are proteins related to engulfment processes through actin-based motility mechanisms [28, 29], that were recently associated with AD resilience according to protein coexpression analysis [39].”

    From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [39]

    The Results sections on protein co-expression and M5 enrichment associate an actin-filament-related protein module with resilience to Alzheimer’s disease. They do not identify ARP2, CAP1, or CFL1 as the proteins associated with resilience; the named resilience-associated actin-related protein is CAPG, not CAP1. The engulfment-mechanism clause is attached to other citations and is not assessed here. (LLM, conf=0.85)

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References 61 · Cited by 37

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Authors
Huang, Z., Merrihew, G. E., Larson, E. B., Park, J., Plubell, D., Fox, E. J., Montine, K. S., Latimer, C. S., Dirk Keene, C., Zou, J. Y., MacCoss, M. J., & Montine, T. J.
Affiliations
  • Stanford Medicine (US)
  • University of Washington (US)
Corresponding author
  • Zou, James Y.
  • MacCoss, Michael J.
  • Montine, Thomas J.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-05-12
Volume
14
Issue
1
Pages
2747-2747
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-38376-x
PMC
PMC10182086
OpenAlex
W4376273794
Cited by
37
References
61
Citations by year
2026: 9 · 2025: 12 · 2024: 10 · 2023: 6
FWCI
6.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Nancy and Buster Alvord Endowment
  • National Institutes of Health (AG066509, AG053959)
  • National Institute on Aging (K08AG065426, U01AG006781, U19AG065156, P30AG066509)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
Keywords
Alzheimer's disease, brain proteomics, soluble amyloid-beta, hippocampus, neocortex, caudate nucleus, protein co-expression networks, cellular detoxification, wound healing, injury response, cognitive impairment, dementia
MeSH terms
Alzheimer Disease, Brain, Hippocampus, Humans, Neocortex, Proteomics, Cognitive Dysfunction

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