Date Available

9-2-2014

Year of Publication

2014

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department/School/Program

Molecular and Cellular Biochemistry

First Advisor

Dr. Michael Paul Murphy

Abstract

The aging brain is prone to the development of pathology and dementia. With a rapidly growing elderly population diagnoses of neurodegenerative diseases, such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), and Parkinson’s disease are on the rise. Additionally, diabetes and obesity are linked to an increased risk of dementia. The convergence of this increasingly aged population with the obesity and diabetes epidemic give rise to new concerns regarding the future of prevention and treatment of neurodegenerative diseases. Our lab has previously shown that leptin, an adipokine involved in signaling satiety to the hypothalamus, can modulate the generation of the amyloid beta (Aβ) peptide (a toxic peptide associated with neurologic disease) and attenuate hyperphosphorylation of the tau protein (another peptide prone to forming large insoluble structures causing neurodegeneration). From these studies we have elucidated that leptin resistant mice (which develop severe obesity and type-2 diabetes mellitus) with knock-in mutations for the amyloid precursor protein (APP) and presenilin-1 (PS1) genes develop extensive vascular pathology and cognitive impairments. Interestingly, these mice do not display increased levels of amyloid deposition in the brain. Additionally, increased tau phosphorylation occurs in these mice with leptin resistance. As a follow up to this study db mice were transduced, via adeno-associated virus, with the tau P301L mutant to induce the development of tangle pathology. These mice displayed no cognitive deficits, yet they displayed increases in both tau phosphorylation and tangle count within the hippocampus. Collectively, these studies indicate leptin resistance, obesity, and type-2 diabetes mellitus promote the development of cerebrovascular and neurofibrillary tangle pathologies associated with neurodegeneration and dementia. These observations open many previously unexplored avenues for developing novel therapeutics to treat these devastating diseases.

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