Date of Award

9-7-2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmacology, Physiology and Therapeutics

First Advisor

Othman Ghribi

Abstract

Alzheimer Disease (AD) is a progressive, debilitating and the most prevalent neurodegenerative disorder affecting 5.5 million people and the sixth leading cause of fatality in the United States. The etiology of AD is not understood and clinically FDA-approved drugs offer only symptomatic relief for a short period of time and in only a subset of AD patients. AD is histopathologically characterized by the presence of extracellular deposits of aggregated Amyloid β (Aβ) peptide as plaques and the intracellular deposition of aggregated hyperphosphorylated tau protein as neurofibrillary tangles (NFT). Leptin, an adipocytokine, has been demonstrated to reduce the genesis of Aβ, hyperphosphorylation of tau, and working memory loss in several in vivo and in vitro paradigms. Furthermore, lower leptin levels have been reported in AD patients are associated with cognitive dysfunction and dementia. However, the mechanisms and signaling cascades involved in the leptin-induced attenuation in Aβ levels as well as mitigation in hyperphosphorylation of tau have not been elucidated. Furthermore, the signal transduction mechanisms and transcription factors that regulate the endogenous expression of leptin in the brain have not been identified. This dissertation demonstrates that decreased levels of leptin may be a significant risk factor for AD. This study shows that the activation of the P13K/Akt/mTORC1 pathway is requisite for leptin expression and represents one of the molecular targets for augmenting endogenous leptin expression and concomitantly reducing Aβ genesis and tau phosphorylation. This study also shows that Endoplasmic Reticulum (ER) Stress negatively regulates leptin expression and agents that preclude or ameliorate ER stress may offer therapeutic incentive by mitigating the reduction in endogenous leptin expression. This study identified the transcription factors CHOP (GADD153) and C/EBPα as the key upstream modulators of leptin expression. Furthermore, the transcription factor NF-κB and the histone deacetylase SIRT1 were identified as key downstream targets of leptin signaling involved in the attenuation of Aβ genesis. Collectively, this study demonstrates that modulation of signal transduction pathways that regulate endogenous leptin expression as well as mediate the leptin-induced salutary effects may represent a unique therapeutic intervention strategy to combat the ravages of AD.

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