P3‐045: Effects of a high‐fat diet on the cerebrovasculature and neuroinflammation in an experimental model of Alzheimer's disease

Abstract

Background:Western diets and mid-life obesity are considered risk factors for developing dementia. Experimentally, such diets increase ADlike pathology and/or behavioural deficits in transgenic mouse models of AD. We have shown that a high-fat diet increases memory deficits in male triple-transgenic (3xTgAD) mice, though the mechanisms underlying this effect are unknown. Several structural and functional cerebrovascular abnormalities are associated with AD, including impaired integrity of the blood brain barrier (BBB) and neurovascular inflammation. A common underlying feature of both obesity and AD is chronic inflammation. The aim of this project is to determine the molecular mechanisms underlying detrimental effects of a high-fat diet on AD, and to test the hypothesis that inflammatory driven changes in cerebrovascular function are crucial. Methods: Groups of male 3xTgAD and control (non-Tg) mice were maintained on a control diet or a high-fat diet for periods from 3to 16 months of age. Overt changes in BBB integrity (IgG), cerebrovascular endothelial activation (intracellular adhesion molecule; ICAM) and neuroinflammation (microglial activation, Iba1) were assessed by immunohistochemistry on brain sections. Brain homogenates from control fed 9-month-old female 3xTgAD and non-Tg mice were used to assess cerebrovascular activation/inflammation (ICAM and vascular adhesion molecule; VCAM) by ELISA. Results: No significant differences were observed in IgG staining in the brains of non-Tg and 3xTgAD male mice on either a control or high-fat diet at all ages tested. Increases in ICAM/VCAM protein expression were identified in the hippocampus of 9-month-old 3xTgAD female mice. However, no differences in the number of ICAM positive vessels between male Non-Tg and 3xTgAD mice on either a control or high-fat diet were identified by immunohistochemistry. Age-related increases in the number of activated microglia were observed in the hippocampus of 3xTgAD when compared to non-Tg control mice. High-fat feeding increased the number of activated microglia in the hippocampus of non-Tg mice but had no effect in 3xTgAD mice.Conclusions: These data suggest that a high-fat diet can induce neuroinflammation in the absence of AD-related pathology and that the mechanisms underlying the detrimental effects of a high-fat diet on behaviour in 3xTgAD mice remain to be resolved.