Recent studies have implicated
resveratrol and
pterostilbene, a
resveratrol derivative, in the protection against age-related diseases including
Alzheimer's disease (AD). However, the mechanism for the favorable effects of
resveratrol in the brain remains unclear and information about direct cross-comparisons between these analogs is rare. As such, the purpose of this study was to compare the effectiveness of diet-achievable supplementation of
resveratrol to that of
pterostilbene at improving functional deficits and AD pathology in the SAMP8 mouse, a model of accelerated aging that is increasingly being validated as a model of sporadic and age-related AD. Furthermore we sought to determine the mechanism of action responsible for functional improvements observed by studying cellular stress,
inflammation, and pathology markers known to be altered in AD. Two months of
pterostilbene diet but not
resveratrol significantly improved radial arm water maze function in SAMP8 compared with control-fed animals. Neither
resveratrol nor
pterostilbene increased
sirtuin 1 (
SIRT1) expression or downstream markers of
sirtuin 1 activation. Importantly, markers of cellular stress,
inflammation, and AD pathology were positively modulated by
pterostilbene but not
resveratrol and were associated with upregulation of
peroxisome proliferator-activated receptor (
PPAR) alpha expression. Taken together our findings indicate that at equivalent and diet-achievable doses
pterostilbene is a more potent modulator of cognition and cellular stress than
resveratrol, likely driven by increased
peroxisome proliferator-activated receptor alpha expression and increased lipophilicity due to substitution of hydroxy with methoxy group in
pterostilbene.