Reduced levels of mitochondrial complex I subunit NDUFB8 and linked complex I + III oxidoreductase activity in the TgCRND8 mouse model of Alzheimer's disease

J Alzheimers Dis. 2014;39(2):347-55. doi: 10.3233/JAD-131499.

Abstract

Bioenergetic failure is a feature of Alzheimer's disease (AD). We examined mitochondrial function in the amyloid-β protein precursor transgenic 'TgCRND8' mouse model of AD. Activities of NADH: cytochrome c reductase (complex I + III) and cytochrome oxidase (complex IV) of the electron transport chain, as well as those of α-ketoglutarate dehydrogenase (α-KGDH) and pyruvate dehydrogenase (PDH) were assessed in brains of 45 week-old mice. Complex I + III activity was reduced by almost 50%, whereas complex IV, α-KGDH, and PDH activities were unaffected. Reduced activity coincided with decreased expression of NDUFB8, a nuclear-DNA encoded subunit integral to the assembly of complex I. The composition and availability of cardiolipin, a major phospholipid in inner mitochondrial membranes, was not altered. To determine whether mitochondrial output is affected by the selective reduction in complex I + III activity, we examined tissue levels of high-energy phosphates. ATP was maintained whereas creatine increased in the cortex and hippocampus. These results suggest disruption of complex I function and the likely role of creatine in sustaining ATP at late stages of dysfunction in TgCRND8 mice.

Keywords: ATP; Alzheimer's disease; NDUFB8; amyloid; cardiolipin; creatine; electron transport chain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Aging
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Cardiolipins / metabolism
  • Cerebral Cortex / metabolism
  • Creatine / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Electron Transport Complex I / metabolism*
  • Electron Transport Complex III / metabolism*
  • Electron Transport Complex IV / metabolism
  • Hippocampus / metabolism
  • Humans
  • Ketoglutarate Dehydrogenase Complex / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Pyruvate Dehydrogenase Complex / metabolism

Substances

  • Amyloid beta-Protein Precursor
  • Cardiolipins
  • NDUFB8 protein, mouse
  • Pyruvate Dehydrogenase Complex
  • Adenosine Triphosphate
  • Ketoglutarate Dehydrogenase Complex
  • Electron Transport Complex IV
  • Electron Transport Complex I
  • Electron Transport Complex III
  • Creatine