EXPLORATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA AGONIST IN ALZHEIMER'S DISEASETHERAPY - A THERAPEUTIC ENIGMA

Abstract

Recent failures of several phase III Alzheimer?s disease (AD) clinical trials that were based on amyloid cascade hypothesis prompted researchers to look for alternatives in understanding the disease and finding an effective treatment for it. Pathological events that are associated with early-stage AD are of particular interest to the AD research community, as these represent potential drug targets that could allow clinical interventions to be initiated while AD has not deteriorated beyond the point of no return. In this thesis, I capitalised the high sensitivity offered by metabolic profiling approach, to study the early-stage AD pathological alterations in AD disease models. I also explored the therapeutic potential of pioglitazone (PIO, a PPAR gamma agonist) in treatment of AD, and demonstrated that (+)-PIO, one of PIO?s stereoisomer, afforded the brain of mice a larger exposure to PIO as compared to racemic PIO itself, suggesting that (+)-PIO is potentially a better drug candidate then racemic PIO for treatment of brain diseases. The findings in this thesis contribute to understanding AD pathogenesis, and support the pursuant of PIO further in the drug pipeline for AD.