ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2018
Synaptotoxicity in Alzheimer's Disease Involved a Dysregulation of Actin Cytoskeleton Dynamics through Cofilin 1 Phosphorylation.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 109 citations in OpenAlex.
- Mitochondrial dysfunction and programmed cell death in Alzheimer's disease: A retrospective bioinformatics study.Medicine · 2026Article
- Coincident Fluorescence-Burst Analysis of Actin Cargo Molecules in Secreted Single Diffusing Extracellular Vesicles From Human Induced Pluripotent Stem Cells.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Cytoskeletal Proteins and Alzheimer's Disease Pathogenesis: Focusing on the Interplay with Tau Pathology.Biomolecules · 2025Review
- Role of LIMK1-cofilin-actin axis in dendritic spine dynamics in Alzheimer's disease.Cell death & disease · 2025Review
- Emerging mechanomedicines informed by mechanotransduction along the integrin-cytoskeleton-nucleus axis.APL bioengineering · 2025Review
- Phytomedicine Potential ofPlants (Basel, Switzerland) · 2025Article
- Structural and functional alterations of neurons derived from sporadic Alzheimer's disease hiPSCs are associated with downregulation of the LIMK1-cofilin axis.Alzheimer's research & therapy · 2024Article
- Impacts of CACNB4 overexpression on dendritic spine density in both sexes and relevance to schizophrenia.Translational psychiatry · 2024Article
- Mitigation of synaptic and memory impairments via F-actin stabilization in Alzheimer's disease.Alzheimer's research & therapy · 2024Article
- Actin depolymerizing factor destrin governs cell migration in neural development during Xenopus embryogenesis.Molecules and cells · 2024Article
- PCDH17 restricts dendritic spine morphogenesis by regulating ROCK2-dependent control of the actin cytoskeleton, modulating emotional behavior.Zoological research · 2024Article
- Cdk12 maintains the integrity of adult axons by suppressing actin remodeling.Cell death discovery · 2023Article
- Article
- Biometals in Alzheimer disease: emerging therapeutic and diagnostic potential of molybdenum and iodine.Journal of translational medicine · 2023Review
- Structural polymorphism and cytotoxicity of brain-derived β-amyloid extracts.Protein science : a publication of the Protein Society · 2023Review
- Novel approaches to increase synaptic resilience as potential treatments for Alzheimer's disease.Seminars in cell & developmental biology · 2023Review
- Policosanol protects against Alzheimer's disease-associated spatial cognitive decline in male rats: possible involved mechanisms.Psychopharmacology · 2023Article
- LIM Kinases, LIMK1 and LIMK2, Are Crucial Node Actors of the Cell Fate: Molecular to Pathological Features.Cells · 2023Review
- Involvement of Paired Immunoglobulin-Like Receptor B in Cognitive Dysfunction Through Hippocampal-Dependent Synaptic Plasticity Impairments in Mice Subjected to Chronic Sleep Restriction.Molecular neurobiology · 2023Article
- ILEE: Algorithms and toolbox for unguided and accurate quantitative analysis of cytoskeletal images.The Journal of cell biology · 2023Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Amyloid-β (Aβ) drives the synaptic impairment and dendritic spine loss characteristic of Alzheimer's disease (AD), but how Aβ affects the actin cytoskeleton remains unknown and contentious. The actin-binding protein, cofilin-1 (cof1), is a major regulator of actin dynamics in dendritic spines, and is subject to phospho-regulation by multiple pathways, including the Rho-associated protein kinase (ROCK) pathway. While cof1 is implicated as a driver of the synaptotoxicity characteristic of the early phases of AD pathophysiology, questions remain about the molecular mechanisms involved. Cofilin-actin rods are observed in neurons exposed to Aβ oligomers (Aβo) and in tissue from AD patients, and others have described an increased cofilin phosphorylation (p-cof1) in AD patients. Here, we report elevated p-cof1 of the postsynaptic enriched fraction of synaptosomes from cortical samples of male APP/PS1 mice and human AD cases of either sex. In primary cortical neurons, Aβo induced rapid actin stabilization and increased p-cof1 in the postsynaptic compartment of excitatory synapses within 30 min. Fluorescence recovery after photobleaching of actin-GFP and calcium imaging in live neurons expressing active or inactive cof1 mutants suggest that cof1 phosphorylation is necessary and sufficient for Aβo-induced synaptic impairment via actin stabilization before the reported formation of cofilin-actin rods. Moreover, the clinically available and well-tolerated ROCK inhibitor, fasudil, prevented Aβo-induced actin stabilization, synaptic impairment, and synaptic loss by blocking cofilin phosphorylation. Aβo also blocked the LTP-induced insertion of the AMPAR subunit, GluA1, at the postsynaptic density, in a fasudil-sensitive manner. These data support an important role for ROCKs and cofilin in mediating Aβ-induced synaptic impairment.
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