ABSTRACT
INTRODUCTION
Cerebrovascular reactivity (CVR) impairment is a key feature of Alzheimer’s disease (AD), but its mechanistic basis remains unclear. This study examined whether vascular smooth muscle cell (VSMC) loss, rather than amyloidosis or neuroinflammation, underlies CVR deficits.
METHODS
Non-contrast MRI, including phase-contrast and pseudo-continuous arterial spin labeling, was performed in mouse models of amyloidosis (5xFAD), VSMC degeneration (CADASIL), and lipopolysaccharide-induced neuroinflammation. Characterization of vascular, amyloid-β, and inflammatory markers were performed for pathological assessment.
RESULTS
CVR impairment emerged only when VSMC loss was present in CADASIL mice and at older ages in 5xFAD mice (9–12 months). Amyloid-β deposition occurred earlier than VSMC loss or CVR decline. Neuroinflammation primarily altered baseline cerebral blood flow without affecting CVR or VSMC integrity.
DISCUSSION
These findings identify VSMC degeneration as an important driver of CVR impairment independent of cerebral amyloid angiopathy or inflammation, highlighting vascular integrity as a potential therapeutic target in AD.
Highlights
Cerebrovascular reactivity (CVR) impairment occurred in 5xFAD mice only when vascular smooth muscle cell (VSMC) loss was present
5xFAD mice exhibited prominent parenchymal but minimal vascular amyloid-β deposition
VSMC developmental deficiency resulted in CVR impairment in a small-vessel disease (SVD) model
Neuroinflammation primarily altered baseline cerebral blood flow (CBF) without affecting CVR
Full Text Availability
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