Synaptic dysfunction, marked by synapse loss and structural changes, is a key contributor to cognitive decline in Alzheimer’s disease (AD). This dysfunction is linked to the loss of the actin cytoskeleton, which provides structural support for synapses. The disruption of actin dynamics compromises synaptic integrity, affecting glutamatergic receptor levels, neurotransmission, and synaptic strength.

In a study using APP/PS1 mice, a model of AD, researchers identified disrupted interactions between PSD-95 and actin, key components of synaptic architecture. Treatment with jasplakinolide, an F-actin stabilizer, restored synaptic actin levels, improved PSD-95-actin association, and increased levels of AMPA and NMDA receptors. This stabilization also enhanced dendritic spine density and reversed memory deficits. Analysis of postmortem human brain tissue from individuals with mild cognitive impairment and AD revealed similar disruptions in PSD-95-actin interactions, reinforcing the clinical relevance. These findings suggest that targeting actin dynamics offers a promising therapeutic approach for addressing synaptic dysfunction and cognitive decline in AD.

Reference: P A H, Basavaraju N, Chandran M, Jaleel A, et al. Mitigation of synaptic and memory impairments via F-actin stabilization in Alzheimer’s disease. Alzheimers Res Ther. 2024 Sep 7;16(1):200. doi: 10.1186/s13195-024-01558-w. PMID: 39244567; PMCID: PMC11380428.