Hypercholesterolemia accelerates amyloid ß-induced cognitive deficits.

ABSTRACT

Hypercholesterolemia is a known risk factor for Alzheimer's disease (AD). In the present study, we investigated whether diet-induced hypercholesterolemia affects AD-like pathologies such as amyloid ß-peptide (Aß) deposition, tau pathology, inflammation and cognitive impairment, using an Aß25-35-injected AD-like pathological mouse model. Hypercholesterolemia was induced by providing apolipoprotein E knock out (Apo E KO) mice with a high-fat diet for 4 weeks prior to Aß25-35 injection and for 4 weeks following Aß25-35 injection, for a total of 8 weeks of treatment. Our data showed that intracerebroventricular injection of C57BL/6J mice with Aß25-35 resulted in increased immunoreactivity of Aß and phosphorylated-tau (p-tau), which was accompanied by enhanced microglial CD11b-like immunoreactivity in the brain. Moreover, hypercholesterolemia slightly increased Aß and p-tau levels and microglial activation in the vehicle group, while further increasing the Aß and p-tau levels and microglial activation in Aß25-35-injected mice. Consistent with the neuropathological analysis, hypercholesterolemia resulted in significant spatial learning and memory deficits in Aß25-35-injected mice as revealed by water maze testing. Collectively, these findings demonstrated that hypercholesterolemia accelerated Aß accumulation and tau pathology, which was accompanied by microglial activation and subsequent aggravation of memory impairment induced by Aß25-35. Thus, we suggest that the modulation of cholesterol can be used to reduce the risk of developing AD.