Resveratrol supplementation and caloric restriction exert sex-specific effects on cerebrovascular function in a rat model of Alzheimer’s Disease

Cerebrovascular dysfunction, including reduced cerebral blood flow (CBF) and cerebrovascular reactivity (CVR), contributes to Alzheimer's disease (AD). Caloric restriction (CR) and resveratrol (Rsv) benefit vascular health, yet their impact on CBF and CVR in AD remains unclear. Here, we investigated the cerebrovascular effects of 40% CR or Rsv supplementation in WT and TgF344-AD rats. Using pseudo-continuous arterial spin labelling (pCASL) MRI, we observed that male Tg control (Ctrl) rats exhibited reduced relative CBF (rCBF) and absolute CBF (aCBF) in the caudate-putamen at baseline compared to WT Ctrl and Tg Rsv rats, while Rsv restored CBF to WT levels. Male Rsv rats also showed higher rCBF than CR rats in the somatosensory cortex, irrespective of genotype. In the cingulate cortex, male Tg rats had lower rCBF than WT, irrespective of treatment. During hypercapnia, Tg males displayed lower rCBF and aCBF across multiple regions, while Rsv increased rCBF in cingulate cortex and somatosensory cortex, regardless of genotype. In females, treatments did not affect baseline or hypercapnic CBF, although CR and Rsv reduced CVR compared to Ctrl. In summary, these findings suggest Rsv reverses AD-related hypoperfusion in males, whereas CR may impair cerebrovascular responsiveness in females, highlighting the need for sex-specific therapeutic strategies.