Exploration of peroxisome proliferator-exploration of peroxisome proliferator-activated receptor gamma agonist in Alzheimer’s disease therapy – a therapeutic enigma

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 earlystage AD pathological alterations in two different AD models, namely Chinese hamster ovarian cells transfected with amyloid precursor protein (CHOAPP695) and transgenic mice carrying APP and presenilin-1 transgenes (APP/PS1). My work in chapter 2 using CHO-APP695 allowed me to detect metabolic changes that occurred prior to any observable accumulation of extracellular amyloid-β in this model. Majority of these metabolic changes were related to impaired energy metabolism and dysregulated amino acid metabolism. Further biochemical assay data supported the notion of mitochondrial dysfunction in this model, and more interestingly I observed an accumulation of APP itself in the mitochondria of CHO-APP695. This abnormal accumulation of APP at mitochondrial membrane could have mangled the powerhouse organelles, hence rendering the cells incapable of efficient respiration, resulting in impaired energy metabolism. Similar trend was observed in APP/PS1 x transgenic mice, where excessive sugar build-up could be detected in their cortex and cerebellum tissue. Coupled with the observations of increased oxidative stress in their cortex, the inefficient energy expenditure and high sugar levels could have contributed to enhancing the oxidation state even further, resulting in subsequent neuronal death and surfacing of AD symptoms. Intriguingly, pioglitazone (PIO) administration was found to have exerted a larger extent of treatment effect than rosiglitazone (ROSI) in CHO-APP695, which was attributed to its dual agonism of both peroxisome proliferatoractivated receptor gamma (PPARγ) and PPAR alpha (PPARα) receptors. PIO treatment was also observed to have successfully rescued the state of impaired energy metabolism in APP/PS1 mice, on top of enhancing the anti-oxidative capacity and lowering the amyloid-β in their cortex tissue. Further work in chapter 4 also showed that P-glycoprotein drug efflux transport at the bloodbrain- barrier is a significant contributor in keeping PIO away from the brain. I went on to show 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. This discovery is particularly relevant now as there are two ongoing clinical trials looking at PIO as treatment for AD and Parkinson’s disease. The findings in my thesis contribute substantially to AD research, and support the pursuant of PIO further in the drug pipeline for AD.Open Acces