ArticleAlzheimer's research & therapy2024
Mitigation of synaptic and memory impairments via F-actin stabilization in Alzheimer's disease.
Article in Alzheimer's research & therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed.
- Suppression of neuronal p27 impairs cognitive function in middle-aged mice.Neurobiology of disease · 2026Article
- A Synonymous DLG4 Variant (c.771G>A) Causes Exon 9 Skipping via Paternal Germline Mosaicism in DLG4-Related Synaptopathy.Molecular genetics & genomic medicine · 2026Article
- Mitochondrial dysfunction and programmed cell death in Alzheimer's disease: A retrospective bioinformatics study.Medicine · 2026Article
- Article
- Early-life cognitive intervention preserves brain function in aged TgF344-AD rats with sex-specific effects.iScience · 2026Article
- Mechanistic insights into the synaptic damage-repair and regeneration processes in neurodegenerative Alzheimer's disease: phytochemicals as neuroprotective agents.Frontiers in synaptic neuroscience · 2026Review
- Metabolic cell death networks in Alzheimer's disease: mechanistic links and therapeutic perspectives of ferroptosis, cuproptosis, and disulfidptosis.Frontiers in cell and developmental biology · 2026Review
- Structures and functions of the MICOS: Pathogenesis and therapeutic implications in Alzheimer's disease.Acta pharmaceutica Sinica. B · 2025Review
- Mossy fiber expression of αSMA in human hippocampus and its relevance to brain evolution and neuronal development.Scientific reports · 2025Article
- From Synaptic Plasticity to Neurodegeneration: BDNF as a Transformative Target in Medicine.International journal of molecular sciences · 2025Review
- Disulfidptosis: a new target for central nervous system disease therapy.Frontiers in neuroscience · 2025Review
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6 authors.
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Abstract
backgroundSynaptic dysfunction, characterized by synapse loss and structural alterations, emerges as a prominent correlate of cognitive decline in Alzheimer's disease (AD). Actin cytoskeleton, which serves as the structural backbone of synaptic architecture, is observed to be lost from synapses in AD. Actin cytoskeleton loss compromises synaptic integrity, affecting glutamatergic receptor levels, neurotransmission, and synaptic strength. Understanding these molecular changes is crucial for developing interventions targeting synaptic dysfunction, potentially mitigating cognitive decline in AD.
methodsIn this study, we investigated the synaptic actin interactome using mass spectrometry in a mouse model of AD, APP/PS1. Our objective was to explore how alterations in synaptic actin dynamics, particularly the interaction between PSD-95 and actin, contribute to synaptic and cognitive impairment in AD. To assess the impact of restoring F-actin levels on synaptic and cognitive functions in APP/PS1 mice, we administered F-actin stabilizing agent, jasplakinolide. Behavioral deficits in the mice were evaluated using the contextual fear conditioning paradigm. We utilized primary neuronal cultures to study the synaptic levels of AMPA and NMDA receptors and the dynamics of PSD-95 actin association. Furthermore, we analyzed postmortem brain tissue samples from subjects with no cognitive impairment (NCI), mild cognitive impairment (MCI), and Alzheimer's dementia (AD) to determine the association between PSD-95 and actin.
resultsWe found a significant reduction in PSD-95-actin association in synaptosomes from middle-aged APP/PS1 mice compared to wild-type (WT) mice. Treatment with jasplakinolide, an actin stabilizer, reversed deficits in memory recall, restored PSD-95-actin association, and increased synaptic F-actin levels in APP/PS1 mice. Additionally, actin stabilization led to elevated synaptic levels of AMPA and NMDA receptors, enhanced dendritic spine density, suggesting improved neurotransmission and synaptic strength in primary cortical neurons from APP/PS1 mice. Furthermore, analysis of postmortem human tissue with NCI, MCI and AD subjects revealed disrupted PSD-95-actin interactions, underscoring the clinical relevance of our preclinical studies.
conclusionOur study elucidates disrupted PSD-95 actin interactions across different models, highlighting potential therapeutic targets for AD. Stabilizing F-actin restores synaptic integrity and ameliorates cognitive deficits in APP/PS1 mice, suggesting that targeting synaptic actin regulation could be a promising therapeutic strategy to mitigate cognitive decline in AD.
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