Academic Journal
Mitigation of synaptic and memory impairments via F-actin stabilization in Alzheimer’s disease
| العنوان: | Mitigation of synaptic and memory impairments via F-actin stabilization in Alzheimer’s disease |
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| المؤلفون: | Haseena P. A., Nimisha Basavaraju, Mahesh Chandran, Abdul Jaleel, David A. Bennett, Reddy Peera Kommaddi |
| المصدر: | Alzheimer’s Research & Therapy, Vol 16, Iss 1, Pp 1-25 (2024) |
| بيانات النشر: | BMC, 2024. |
| سنة النشر: | 2024 |
| المجموعة: | LCC:Neurosciences. Biological psychiatry. Neuropsychiatry LCC:Neurology. Diseases of the nervous system |
| مصطلحات موضوعية: | Synaptic dysfunction, Synaptic actin interactome, Post synaptic density, F-actin loss, Alzheimer’s disease, APP/PS1, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429 |
| الوصف: | Abstract Background Synaptic 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. Methods In 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. Results We 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. Conclusion Our 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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1758-9193 |
| Relation: | https://doaj.org/toc/1758-9193 |
| DOI: | 10.1186/s13195-024-01558-w |
| URL الوصول: | https://doaj.org/article/4118cad1979b48aa8bca305d7a19146c |
| رقم الانضمام: | edsdoj.4118cad1979b48aa8bca305d7a19146c |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 17589193 |
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| DOI: | 10.1186/s13195-024-01558-w |