Date of Graduation

2016

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Neurology

Committee Chair

Bernard G Schreurs

Committee Co-Chair

Albert S Berrebi

Committee Member

Gregory W Konat

Committee Member

David P Siderovski

Committee Member

James W Simpkins

Abstract

High serum cholesterol levels in midlife have been associated with an increased risk of developing Alzheimer's disease (AD) later in life. This thesis investigates a possible mechanism linking dietary cholesterol, which cannot pass the blood brain barrier, and AD-like hippocampal neuropathology. The first study tested the hypothesis that a high cholesterol diet increases the flux of the cholesterol metabolite 27-hydroxycholesterol (27-OHC) into the hippocampus. We found that a high-cholesterol diet increased levels of 27-OHC, a biologically active circulatory breakdown product of cholesterol, in hippocampal tissue. 27-OHC has been identified as an endogenous selective estrogen receptor modulator (SERM) that affects estrogen signaling pathways in a tissue-dependent manner. Estrogen-mediated non-reproductive functions require estrogen receptors (ERs) and include modulation of mitochondrial function and structure, as well as regulation of synaptogenesis in the brain. In the second study we hypothesized that the expression of ER's in hippocampus will change following a high-cholesterol diet and that estrogen-dependent neuroprotection will be compromised. We found that the high-cholesterol diet and resulting increase of 27-OHC in the brain were associated with changes in the expression of ER's, decreased mitochondrial content and synaptic densities as well as increased neuronal degeneration in the hippocampus. In the third study we assessed the correlations between the levels of 27-OHC and ER expression and we found that high 27-OHC levels in the hippocampus are positively correlated with levels of ERbeta and negatively correlated with expression of mitochondrial protein. We also found a positive correlation between PSD-95, a synaptic marker, levels and performance on a memory test, and a negative correlation between ERbeta expression and mitochondrial protein levels. This suggests that 27-OHC might be a molecule that modulates ER signaling and results in loss of estrogen-related neuroprotection.

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