Mitochondrial abnormalities in Alzheimer brain: Mechanistic implications

TLDR

Reductions in cerebral metabolism that impair cognition in normal individuals also occur in Alzheimer’s disease, and the degree of clinical disability correlates with the magnitude of this metabolic decline. The study tested whether impairments in mitochondrial TCA cycle enzymes correlate with disability in AD. Brains from autopsy‑confirmed AD patients with known clinical dementia ratings were examined for TCA cycle enzyme activities. Activities of pyruvate dehydrogenase complex, isocitrate dehydrogenase, and α‑ketoglutarate dehydrogenase complex were significantly decreased (−41%, −27%, −57%) while succinate dehydrogenase and malate dehydrogenase were increased (+44%, +54%) and all changes correlated with clinical state, with the strongest correlation for pyruvate dehydrogenase complex (r=0.77). Ann Neurol 2005;57:695–703.

Abstract

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