Dietary Quercetin Ameliorates Memory Impairment in a Murine Model of Alzheimer’s Disease with Obesity and Diabetes, Suppressing ATF4 Expression

Abstract

Background: While type 2 diabetes is a known risk factor for Alzheimer’s disease (AD), the underlying mechanism of this relationship remains unclear. In a previous study, we demonstrated that brain expression of activating transcription factor 4 (ATF4) is increased in aged (12- month-old) amyloid-β precursor protein (APP) 23 mice (APP) and in the young (3-month-old) offspring of APP mice crossed with obese and diabetic db/db mice (APP;db/db). On this premise, we examined the relationship between ATF4 expression and memory in APP;db/db mice. Methods and Findings: We demonstrate that ATF4 expression at 6-9 months of age was higher in the brains of APP;db/db mice than that in the brains of non-obese APP mice. Both APP and APP;db/db mice learned to discriminate contextual and auditory cues in contextual and auditory fear conditioning. However, novel object recognition (NOR) memory was impaired in APP;db/db mice, but was unaffected in APP mice. Five weeks of dietary supplementation with quercetin, which is a polyhydroxylated flavonoid, ameliorated NOR memory deficits in APP;db/db mice in association with suppressed ATF4 expression in the brain. Conclusion: These results indicate that dietary quercetin suppresses the obesity-induced ATF4 expression in the brain. Therefore, control of the integrated stress response (ISR) with biologically active compounds that reduce ATF4, such as quercetin, may be valuable for the treatment of memory impairments in early-stage AD, and particularly in cases with comorbid obesity and/or diabetes.