CHANGES IN ASTROCYTE FUNCTIONAL MARKERS AND β-AMYLOID METABOLISM-RELATED PROTEINS IN THE EARLY STAGES OF HYPERCHOLESTEROLEMIA

Cholesterol is an essential substance for maintaining normal structure and function of the brain. But unfortunately, a long-term high-cholesterol diet can lead to a variety of pathological changes of the brain such as beta-amyloid (A beta) accumulation, Tau hyperphosphorylation, reactive gliosis, neuroinflammation, neuronal death and synaptic degeneration. These pathological changes have complex internal relations with one other, causingmemory impairment and participating in the pathogenesis of Alzheimer's disease (AD). However, early hypercholesterolemia-induced events that lead to brain deterioration are not clear. To address this, 6-month-old female mice were fed a 3% cholesterol diet for 8 weeks, followed by behavioral, biochemical and neuropathological analyses. The high-cholesterol-fed mice did not show neuronal and synaptic impairment or cognitive deficits compared with mice given a normal diet, but astrocytes were mildly activated with increased expression of functional markers including apolipoprotein E and aquaporin 4 in the hippocampus. Hippocampal interleukin-1 beta expression slightly increased, but interleukin-6 (IL-6) and tumor necrosis factor-alpha did not change significantly compared with those in the control group. Levels of A beta, and its precursor protein, were unaffected, but levels of presenilin 1 and insulin-degrading enzyme (IDE), that initiate A beta generation and degradation, respectively, increased in the hippocampus of the model mice. In addition, Tau phosphorylation levels were not different between the control and model groups. These results suggest that changes in astrocyte functional markers and A beta metabolism proteins, which contribute to maintaining brain cholesterol and A beta homeostasis, are early events in the process of hypercholesterolemia-related neuropathological changes. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.