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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.

This case report describes a 43-year-old female with a heterozygous mutation in the HTRA1 gene (905G>A, Arg302Gln) who exhibited all typical features of CARASIL, including baldness, recurrent ischemic strokes, lumbago, headache, and dementia, along with severe clinical symptoms and rapid progression. Despite heterozygous mutations usually being non-pathogenic or causing milder symptoms, this patient experienced significant cognitive decline, motor function loss, and was bedridden for over a year. The findings suggest that heterozygous mutations in HTRA1 can also result in typical CARASIL features, expanding the understanding of the disease.