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Mitochondrial abnormalities in Alzheimer brain: Mechanistic implications
Author(s) -
Bubber Parvesh,
Haroutunian Vahram,
Fisch Gene,
Blass John P.,
Gibson Gary E.
Publication year - 2005
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.20474
Subject(s) - citric acid cycle , isocitrate dehydrogenase , pyruvate dehydrogenase complex , malate dehydrogenase , succinate dehydrogenase , mitochondrion , dementia , alzheimer's disease , enzyme , oxoglutarate dehydrogenase complex , metabolism , biology , biochemistry , disease , medicine , dehydrogenase , endocrinology , pyruvate dehydrogenase phosphatase
Abstract Reductions in cerebral metabolism sufficient to impair cognition in normal individuals also occur in Alzheimer's disease (AD). The degree of clinical disability in AD correlates closely to the magnitude of the reduction in brain metabolism. Therefore, we tested whether impairments in tricarboxylic acid (TCA) cycle enzymes of mitochondria correlate with disability. Brains were from patients with autopsy‐confirmed AD and clinical dementia ratings (CDRs) before death. Significant ( p < 0.01) decreases occurred in the activities of the pyruvate dehydrogenase complex (−41%), isocitrate dehydrogenase (−27%), and the α‐ketoglutarate dehydrogenase complex (−57%). Activities of succinate dehydrogenase (complex II) (+44%) and malate dehydrogenase (+54%) were increased ( p < 0.01). Activities of the other four TCA cycle enzymes were unchanged. All of the changes in TCA cycle activities correlated with the clinical state ( p < 0.01), suggesting a coordinated mitochondrial alteration. The highest correlation was with pyruvate dehydrogenase complex ( r = 0.77, r 2 = 0.59). Measures to improve TCA cycle metabolism might benefit AD patients. Ann Neurol 2005;57:695–703