Systemic delivery of synapsin‐promoted caveolin‐1 overexpression ameliorates pathological TDP‐43–induced cognitive decline and neurodegenerative changes

INTRODUCTION 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. METHODS 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. RESULTS 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. DISCUSSION 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.