Systemic delivery of synapsin-promoted caveolin-1 overexpression ameliorates pathological TDP-43-induced cognitive...

Transactive response DNA-binding protein 43 (TDP-43) proteinopathy is associated with frontotemporal dementia and Alzheimer's disease (AD). We previously demonstrated that synapsin-promoted caveolin-1 (SynCav1) preserves cognitive function in the mouse model of AD. This study investigated the therapeutic potential of SynCav1 in a mouse model of TDP-43 proteinopathy.

AAV-PhP.eB-SynCav1 was delivered systemically to the TDP-43^A315T mouse, followed by cognitive evaluation and biochemical and ultrastructural analysis of brain tissue.

SynCav1 exerted robust neuroprotective effects on cognition. Mechanistically, pathological TDP-43 mislocalized to membrane lipid rafts (MLRs), resulting in decreased MLR-associated GluN2A expression and degenerative changes in neuronal ultrastructure. In contrast, SynCav1 delivery alleviated TDP-43 mislocalization on MLRs, stabilized MLR-associated GluN2A expression, and preserved synaptic ultrastructure. Furthermore, SynCav1 mitigated TDP-43-induced mitochondrial hyper-fragmentation and excessive mitochondrial fission signaling.

These findings establish a novel link between TDP-43 proteinopathy and MLR instability, supporting SynCav1 as a "neuron-centric" candidate for treating TDP-43-related neurodegeneration.