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

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 ( -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 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 -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 -KI mice.

CONCLUSIONS

Our findings demonstrate that the -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.