Reverting Metabolic Dysfunction in Cortex and Cerebellum of APP/PS1 Mice, a Model for Alzheimer's Disease by Pioglitazone, a Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Agonist

Identification of molecular mechanisms underlying early-stage Alzheimer's disease (AD) is important for the development of new therapies against and diagnosis of AD. In this study, gas chromatography time-of-flight mass spectrometry (GC-TOF-MS)-based metabolomics approach was employed to investigate the metabolic profiles in plasma and brain tissues harvested from 5-month-old APP/PS1 transgenic mice and their wildtype counterparts. Since different brain regions were expected to have their own distinct metabolic signals, four different brain regions, namely cortex, hippocampus, midbrain and cerebellum tissues, were dissected and had their metabolic profiles studied separately. Biochemical assays were also performed on plasma and brain cortex tissue of transgenic mice and wildtype mice, with a focus on mitochondrial health. Amyloid precursor protein and amyloid-beta levels in plasma, brain cortex tissue and mitochondria fractions isolated from brain cortex were measured to assess the amyloid pathology. Our findings include the observation of extensive metabolic alterations in cortex and cerebellum of APP/PS1 mice, but not in their hippocampus, midbrain and plasma. The major pathways affected in cortex and cerebellum of APP/PS1 mice were closely related to impaired energy metabolism and perturbation of amino acid metabolism in these mice. APP/PS1 mice also exhibited higher amyloid-beta 40 and amyloid-beta 42 in their cortex, accumulation of mitochondria APP in their cortex, and presented an altered oxidative state in their brain. Treatment with the peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist pioglitazone (PIO) successfully restored the energy metabolism, lowered amyloid-beta levels and afforded the APP/PS1 mice a better antioxidative capacity in their cortex.