All ETDs from UAB

Advisory Committee Chair

Ling Li

Advisory Committee Members

Lori L McMahon

Robin Lester

Erik Roberson

Linda Wadiche

Scott Wilson

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Statins, a widely prescribed class of cholesterol-lowering drug, inhibit HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway. Due to the identification of cholesterol as a risk factor for developing Alzheimer's disease (AD), a number of studies have examined whether statins are neuroprotective against developing AD or dementia. While some epidemiological studies do indicate a lower prevalence of AD in people taking statins, other reports are contradictory. A consensus has therefore not been reached regarding the neuroprotective effects of statin treatment. Aside from the well-characterized reduction in circulating cholesterol resulting from statin therapy, numerous cholesterol-independent, pleiotropic effects have been observed in the central nervous system (CNS). These include enhanced neurogenesis in the dentate gyrus, improved cerebral blood flow, augmented functional recovery from cerebral ischemia and enhanced neurite outgrowth. The mechanisms underlying many pleiotropic effects are derived from altered isoprenylation of signaling molecules, including small GTPases. In light of data showing dramatic improvements in learning and memory in wild-type mice after statin treatment, the current study was conducted to elucidate how a lipophilic statin, simvastatin (SV), affects long-term potentiation (LTP) in the hippocampus of young adult mice. It is shown that in vitro SV treatment for several hours increases the magnitude of LTP at CA3-CA1 synapses in a manner independent of changes in basal synaptic transmission, as neither paired-pulse ratios, nor input/output curves were affected by SV. Also, it is determined that SV-mediated LTP enhancement is dependent upon PI3-K activation during the induction phase. Furthermore, data are presented suggesting SV increases LTP by decreasing farnesylation of isoprenylated proteins, and that inhibiting farnesyl transferase promotes recruitment of PI3-K to the induction of LTP. Overall, the present study provides a framework for understanding how SV affects the mechanisms of synaptic plasticity in the adult hippocampus and highlights the need for further investigation into how isoprenylation might affect cognitive function in statin-prescribed populations.

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