Cerebrovascular alterations in a mouse model of late-onset Alzheimer's disease.

Abstract

Significance: Alzheimer's disease (AD) is an age-related neurodegenerative disorder with cerebrovascular alterations contributing to cognitive decline. Assessing cerebrovascular changes in mouse models that mimic the human condition of late-onset, sporadic AD is important for better human applicability.

Aim: To assess cerebrovascular changes in three mouse models: (1) 3xTg-AD; (2) the humanized amyloid-beta knock-in ( $\mathrm{hA}\beta$ -KI) mouse model of late-onset, sporadic AD; and (3) age-matched wild-type mice.

Approach: We measured resting-state cerebral blood flow (CBF) and neurovascular coupling (NVC) using laser speckle imaging (LSI) and performed ex vivo analyses of gene expression and cerebrovascular structure using bulk ribonucleic acid sequencing and confocal microscopy, respectively.

Results: Our study identifies specific cerebrovascular alterations in the $\mathrm{hA}\beta$ -KI mouse model, including increased resting-state CBF, a shift toward smaller blood vessel diameters, impaired NVC, and transcriptomic changes related to metabolism and inflammation. Notably, we found that the increased resting-state CBF was primarily associated with female $\mathrm{hA}\beta$ -KI mice.

Conclusions: Our findings demonstrate that the $\mathrm{hA}\beta$ -KI mouse model exhibits cerebrovascular alterations that warrant further investigation to uncover the underlying mechanisms. Expanding these studies could enhance our understanding of cerebrovascular alterations in AD and support the development of targeted therapeutic strategies.