HtrA1L364P Leads to Cognitive Dysfunction and Vascular Destruction Through TGF-β/Smad Signaling Pathway in CARASIL Model Mice

This study investigates the pathogenesis of CARASIL using a mouse model with the HtrA1L364P mutation. Behavioral tests showed significant cognitive impairments in the mutant mice compared to wild-type mice (p < 0.001). Pathological analysis revealed structural abnormalities in brain arterioles, reduced synapses, thickened vessel walls, and other cellular anomalies. Molecular studies indicated increased mRNA and protein levels of TGF-β, Smad2, and Smad3 in the mutant mice's brains. The findings suggest that the TGF-β/Smad signaling pathway is abnormally upregulated in CARASIL, contributing to cognitive dysfunction and vascular damage. This model provides a valuable tool for exploring CARASIL pathogenesis and potential therapies.