Systemic delivery of synapsin‐promoted caveolin‐1 overexpression ameliorates pathological TDP‐43–induced cognitive decline and neurodegenerative changes
Year: 2026
Type: article
Abstract: 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: 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.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.71450
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,200
Awards: G2128927816, G3341983367, G4631133815, Mentored Career Development Program, CTSA UM1 Program at University of California San Diego Altman Clinical and Translational Research Institute, CTSA K12 Program at University of California San Diego Altman Clinical and Translational Research Institute
OpenAlex ID: W7162413652