Graduation Date

5-2014

Document Type

Master's Thesis

Degree Name

Master of Science

Department or Program

Biological Sciences

Department or Program Chair

Mary B. Sevigny, Ph.D.

First Reader

Dale E. Bredesen, M.D.

Second Reader

Kenneth Frost, Ph.D.

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder whose exact cause(s) are still unknown. Εpsilon 4, an allele of apolipoprotein E (ApoE4), is currently the most important risk factor for Alzheimer’s disease. Individuals that inherit two copies of the ApoE ε4 allele have an approximately ten to thirty times increased risk of developing AD in comparison to persons not carrying this allele. This association may relate to ApoE4’s susceptibility to proteolysis and neurotoxicity. Amyloid precursor protein (APP) is involved with neurite extension and neurite retraction, and has been shown to function as a molecular switch with two separate cleavage patterns. Cleavage at the β-, γ-, and caspase sites results in the production of four neurotoxic, pro-apoptotic, pro-AD peptides: sAPPβ, Aβ, Jcasp, and C31. In contrast, anti-AD cleavage at the α-site produces two neuroprotective peptides: sAPPα and αCTF. Recent data have shown significantly lower sAPPα levels in cerebrospinal fluid of AD patients who possess one or more ε4 allele. Recent research studies have focused attention on Sirtuins. SirT1 plays a role in synaptic plasticity, learning and memory. Additionally, it has been demonstrated to reduce Aβ accumulation and elevate α-secretase activity. ApoE4 has been suggested to decrease SirT1. SirT1 suppresses AD in cells, primary neurons, and mouse models, by activating transcription of ADAM10, thus increasing the levels of the neuroprotective sAPPα, which is the pro-ligand peptide. In addition, overexpression of SirT1 causally promotes α-secretase activity and attentuates Aβ peptides generation in primary neuron cultures. Using various methods, SirT1 demonstrates having an effect on ApoE4 and may have an interaction either directly or indirectly.

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