TY - JOUR
T1 - Shift in brain metabolism in late onset Alzheimer's disease
T2 - Implications for biomarkers and therapeutic interventions
AU - Yao, Jia
AU - Rettberg, Jamaica R.
AU - Klosinski, Lauren P.
AU - Cadenas, Enrique
AU - Brinton, Roberta Diaz
N1 - Funding Information:
This study was supported by National Institute on Aging Grant 2R01AG032236 (to RDB) National Institute on Aging Grant 5P01AG026572 (to RDB; Project 1 to EC and RDB) and Eileen L. Norris Foundation (to RDB).
PY - 2011/8
Y1 - 2011/8
N2 - Alzheimer's is a neurodegenerative disease with a complex and progressive pathological phenotype characterized first by hypometabolism and impaired mitochondrial bioenergetics followed by pathological burden. Increasing evidence indicates an antecedent and potentially causal role of mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress in AD pathogenesis. Compromised mitochondrial bioenergetics lead to over-production of and mitochondrial accumulation of β-amyloid, which is coupled with oxidative stress. Collectively, this results in a shift in brain metabolic profile from glucose-driven bioenergetics towards a compensatory, but less efficient, ketogenic pathway. We propose that the compensatory shift from a primarily aerobic glycolysis pathway to a ketogenic/fatty acid β-oxidation pathway eventually leads to white matter degeneration. The essential role of mitochondrial bioenergetics and the unique trajectory of compensatory metabolic adaptations in brain enable a bioenergetic-centric strategy for development of biomarkers. From a therapeutic perspective, this trajectory of alterations in brain metabolic capacity enables disease-stage specific strategies to target brain metabolism for disease prevention and treatment. A combination of nutraceutical and pharmaceutical interventions that enhance glucose-driven metabolic activity and potentiate mitochondrial bioenergetic function could prevent the antecedent decline in brain glucose metabolism, promote healthy aging and prevent AD. Alternatively, during the prodromal incipient phase of AD, sustained activation of ketogenic metabolic pathways coupled with supplementation of the alternative fuel source, ketone bodies, could sustain mitochondrial bioenergetic function to prevent or delay further progression of the disease.
AB - Alzheimer's is a neurodegenerative disease with a complex and progressive pathological phenotype characterized first by hypometabolism and impaired mitochondrial bioenergetics followed by pathological burden. Increasing evidence indicates an antecedent and potentially causal role of mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress in AD pathogenesis. Compromised mitochondrial bioenergetics lead to over-production of and mitochondrial accumulation of β-amyloid, which is coupled with oxidative stress. Collectively, this results in a shift in brain metabolic profile from glucose-driven bioenergetics towards a compensatory, but less efficient, ketogenic pathway. We propose that the compensatory shift from a primarily aerobic glycolysis pathway to a ketogenic/fatty acid β-oxidation pathway eventually leads to white matter degeneration. The essential role of mitochondrial bioenergetics and the unique trajectory of compensatory metabolic adaptations in brain enable a bioenergetic-centric strategy for development of biomarkers. From a therapeutic perspective, this trajectory of alterations in brain metabolic capacity enables disease-stage specific strategies to target brain metabolism for disease prevention and treatment. A combination of nutraceutical and pharmaceutical interventions that enhance glucose-driven metabolic activity and potentiate mitochondrial bioenergetic function could prevent the antecedent decline in brain glucose metabolism, promote healthy aging and prevent AD. Alternatively, during the prodromal incipient phase of AD, sustained activation of ketogenic metabolic pathways coupled with supplementation of the alternative fuel source, ketone bodies, could sustain mitochondrial bioenergetic function to prevent or delay further progression of the disease.
KW - Alzheimer's disease
KW - Bioenergetics
KW - Biomarkers
KW - Mitochondria
KW - Oxidative stress
KW - White matter degeneration
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U2 - 10.1016/j.mam.2011.10.005
DO - 10.1016/j.mam.2011.10.005
M3 - Article
C2 - 22024249
AN - SCOPUS:81855164838
SN - 0098-2997
VL - 32
SP - 247
EP - 257
JO - Molecular Aspects of Medicine
JF - Molecular Aspects of Medicine
IS - 4-6
ER -