Gene expression and brain pathology at the early stages of bilateral chronic cerebral hypoperfusion in the female mouse brain.

Chronic cerebral hypoperfusion (CCH) is a major risk factor for neurodegenerative diseases, including vascular dementia (VD). It is well documented that sex differences account for variability in progression and outcomes in cerebrovascular pathophysiology and dementia risk. Despite extensive study of VD, most mechanistic and preclinical work has been conducted in male animals, leaving the molecular and cellular consequences of CCH in the female brain largely unexplored. To address this critical gap in knowledge, we investigated the effects of short-term CCH on pathology and gene expression changes in 6-7-month-old female C57BL/6 J mice using the bilateral common carotid artery stenosis (BCAS) mouse model. Thirty days following BCAS surgery, the mice exhibited early pathological changes such as pyknotic nuclei and moderate white matter damage, cellular changes such as astrocytic activation and clusters of degenerating neurons in the cortex and hippocampus, and gene expression alterations primarily related to extracellular matrix remodeling and mRNA splicing, with no significant changes in hippocampal-dependent spatial working memory. Together, our study demonstrates that pathological changes in the female brain begin to emerge as early as 30-35 days of continuous CCH.