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.