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Cited by 99Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology Research

Slingshot-Cofilin activation mediates mitochondrial and synaptic dysfunction via Aβ ligation to β1-integrin conformers

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Woo, J A, Zhao, X, Khan, H, Penn, C, Wang, X, Joly-Amado, A, Weeber, E, Morgan, D +1 more·2015·Cell Death & Differentiation
DOI 10.1038/cdd.2015.5PMC PMC4423195
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Abstract

The accumulation of amyloid-β protein (Aβ) is an early event associated with synaptic and mitochondrial damage in Alzheimer's disease (AD). Recent studies have implicated the filamentous actin (F-actin) severing protein, Cofilin, in synaptic remodeling, mitochondrial dysfunction, and AD pathogenesis. However, whether Cofilin is an essential component of the AD pathogenic process and how Aβ impinges its signals to Cofilin from the neuronal surface are unknown. In this study, we found that Aβ42 oligomers (Aβ42O, amyloid-β protein 1-42 oligomers) bind with high affinity to low or intermediate activation conformers of β1-integrin, resulting in the loss of surface β1-integrin and activation of Cofilin via Slingshot homology-1 (SSH1) activation. Specifically, conditional loss of β1-integrin prevented Aβ42O-induced Cofilin activation, and allosteric modulation or activation of β1-integrin significantly reduced Aβ42O binding to neurons while blocking Aβ42O-induced reactive oxygen species (ROS) production, mitochondrial dysfunction, depletion of F-actin/focal Vinculin, and apoptosis. Cofilin, in turn, was required for Aβ42O-induced loss of cell surface β1-integrin, disruption of F-actin/focal Talin-Vinculin, and depletion of F-actin-associated postsynaptic proteins. SSH1 reduction, which mitigated Cofilin activation, prevented Aβ42O-induced mitochondrial Cofilin translocation and apoptosis, while AD brain mitochondria contained significantly increased activated/oxidized Cofilin. In mechanistic support in vivo, AD mouse model (APP (amyloid precursor protein)/PS1) brains contained increased SSH1/Cofilin and decreased SSH1/14-3-3 complexes, indicative of SSH1-Cofilin activation via release of SSH1 from 14-3-3. Finally, genetic reduction in Cofilin rescued APP/Aβ-induced synaptic protein loss and gliosis in vivo as well as deficits in long-term potentiation (LTP) and contextual memory in APP/PS1 mice. These novel findings therefore implicate the essential involvement of the β1-integrin-SSH1-Cofilin pathway in mitochondrial and synaptic dysfunction in AD.

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Authors
Woo, J. A., Zhao, X., Khan, H., Penn, C., Wang, X., Joly-Amado, A., Weeber, E., Morgan, D., & Kang, D. E.
Affiliations
University of South Florida (US)
Corresponding author
Kang, D E
ORCID
Venue
Cell Death & Differentiation
Publisher
Springer Science and Business Media LLC
Published
2015-02-20
Volume
22
Issue
6
Pages
921-934
ISSN
  • 1350-9047 (ISSN-L)
  • 1476-5403
DOI
10.1038/cdd.2015.5
PMC
PMC4423195
OpenAlex
W1979730343
Cited by
99
References
6
Citations by year
2026: 6 · 2025: 5 · 2024: 5 · 2023: 9 · 2022: 16 · 2021: 10 · 2020: 12 · 2019: 11 · 2018: 7 · 2017: 11 · 2016: 6 · 2015: 1
FWCI
5.56
Type
journal article
Language
en
Update notices
Open access
Licence
Locations
  • Cell Death and Differentiation (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Florida Department of Health (5AZ07)
  • National Institutes of Health
  • National Institute on Aging (K02AG031920, R01AG033055)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
Alzheimer's disease, amyloid-beta, cofilin, beta1 integrin, SSH1, mitochondrial dysfunction, synaptic dysfunction, reactive oxygen species, apoptosis, APP/PS1 mice, long-term potentiation, contextual memory, gliosis, postsynaptic proteins
MeSH terms
Animals, Cell Line, Cricetulus, Electrophysiology, Hippocampus, Humans, Mitochondria, Phosphoprotein Phosphatases, Protein Binding, Synapses, Immunoblotting, Amyloid beta-Peptides, CHO Cells, Apoptosis, Reactive Oxygen Species, Integrin beta1, Actin Depolymerizing Factors, Mice

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