Post synaptic density 95 (PSD95)–Actin interaction: A critical regulator of synaptic strength and plasticity in Alzheimer’s disease pathology

Abstract

AbstractBackgroundPSD95 serves as a scaffolding protein to several neurotransmitter receptors, signal transduction components, and adhesion molecules at the synapse. It is a potential regulator of synaptic strength and plasticity by regulating glutamatergic receptor trafficking, which is impaired in AD. PSD95 interacts directly with NMDA receptors while the interactions with AMPA receptors are through an auxiliary subunit TARPs. Actin cytoskeleton is highly enriched at the synapse. However, the interaction of PSD‐95 – actin and its consequences in synaptic transmission is not understood. Therefore, we investigated the critical role of PSD‐95 association at the synapse with actin and its impact on AMPA and NMDA receptors using AD mice.MethodsSynaptosomes were isolated from adolescent and middle aged wildtype and APP/PS1 mice. Immunoprecipitation was performed using the synaptosomes and F‐actin fractions with anti‐PSD95 antibody followed immunoblotting against glutamatergic receptor subunit antibodies and actin antibody. Statistical comparisons between two groups were performed with the two‐tailed unpaired Mann–Whitney U test.ResultsPSD95 association with actin is detected in synaptosomes isolated from adolescent and middle aged WT and APP/PS1 mouse brain cortex. We found that PSD95‐actin association is significantly decreased in middle aged APP/PS1 mice compared with WT while it remains unaffected in the F‐actin fraction of synaptosomes in APP/PS1 mice. Then, we examined the levels of AMPA and NMDA receptor subunits in APP/PS1 mice. GluA1 and GluA2 subunits of AMPAR are significantly decreased in middle aged but not in adolescent APP/PS1 mice in comparison to age matched WT mice. Protein levels of GluN1 and GluN2B subunits are significantly decreased in both adolescent and middle aged APP/PS1 mice, while GluN2A levels are reduced only in adolescent mice. We detected that PSD95 is physically associated with both AMPAR and NMDAR subunits and this association with GluA1 subunit is affected only in middle aged APP/PS1 mice. Interestingly, interaction of NMDAR subunits (GluN1 and GluN2B) with PSD‐95 is greatly enhanced at adolescent APP/PS1 mice even though these subunit protein levels are significantly diminished.ConclusionOur findings indicate that perturbation of PSD95‐actin association and glutamatergic receptors in AD leads to synaptic dysfunction. It may have critical implications in defective glutamatergic neurotransmission.