Cholesterol profiling reveals 7β-hydroxycholesterol as a pathologically relevant peripheral biomarker of Alzheimer's disease

Abstract

Aim: Cholesterol homeostasis is associated with Alzheimer's disease (AD). Despite the multitude of cholesterol metabolites, little is known about which metabolites are directly involved in AD pathogenesis and can serve as its potential biomarkers. Methods: To identify "hit" metabolites, steroid profiling was conducted in mice with different age, diet, and genotype and also in humans with normal cognition, mild cognitive impairment, and AD using gas chromatography-mass spectrometry. Then, using one of the "hit" molecules (7 beta-hydroxycholesterol; OHC), molecular and histopathological experiment and behavioral testing were conducted in normal mice following its intracranial stereotaxic injection to see whether this molecule drives AD pathogenesis and causes cognitive impairment. Results: The serum levels of several metabolites, including 7 beta-OHC, were increased by aging in the 3xTg-AD unlike normal mice. Consistently, the levels of 7 beta-OHC were increased in the hairs of patients with AD and were correlated with clinical severity. We found that 7 beta-OHC directly affects AD-related pathophysiology; intrahippocampal injection of 7 beta-OHC induced astrocyte and microglial cell activation, increased the levels of pro-inflammatory cytokines (TNF-alpha, IL-1 beta, IL-6), and enhanced amyloidogenic pathway. Mice treated with 7 beta-OHC also exhibited deficits in memory and frontal/executive functions assessed by object recognition and 5-choice serial reaction time task, respectively. Conclusions: Our results suggest that 7 beta-OHC could serve as a convenient, peripheral biomarker of AD. As directly involved in AD pathogenesis, 7 beta-OHC assay may help actualize personalized medicine in a way to identify an at-risk subgroup as a candidate population for statin-based AD treatment.