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

Autor: Shili Yang, Hai Ning Pee, Ling Rong Wong, Paul C. Ho, Kai Lun Chang
Rok vydání: 2018
Předmět:
0301 basic medicine
Agonist
Genetically modified mouse
Male
Cerebellum
medicine.medical_specialty
medicine.drug_class
Neuroscience (miscellaneous)
Peroxisome proliferator-activated receptor
Mice
Transgenic
Citrate (si)-Synthase
Mitochondrion
Hippocampus
Midbrain
03 medical and health sciences
Cellular and Molecular Neuroscience
Amyloid beta-Protein Precursor
0302 clinical medicine
Alzheimer Disease
Internal medicine
mental disorders
medicine
Amyloid precursor protein
Presenilin-1
Animals
Metabolomics
Receptor
chemistry.chemical_classification
Cerebral Cortex
Principal Component Analysis
biology
L-Lactate Dehydrogenase
Pioglitazone
Superoxide Dismutase
Discriminant Analysis
Catalase
Mitochondria
PPAR gamma
Disease Models
Animal
030104 developmental biology
medicine.anatomical_structure
Endocrinology
nervous system
Neurology
chemistry
biology.protein
Female
030217 neurology & neurosurgery
Zdroj: Molecular neurobiology. 56(11)
ISSN: 1559-1182
Popis: 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-β 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-β40 and amyloid-β42 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 (PPARγ) agonist pioglitazone (PIO) successfully restored the energy metabolism, lowered amyloid-β levels and afforded the APP/PS1 mice a better antioxidative capacity in their cortex.
Databáze: OpenAIRE
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