Pathogenic role of mitochondrial amyloid-β peptide

Abstract

Metabolic dysfunction is one of the early features in Alzheimer’s disease (AD) affected brain. Amyloid-β peptide (Aβ), a major peptide deposited in neuritic plaques, has been considered as an important initiating molecule in the pathogenesis of AD. However, the pathogenic role of Aβ remains to be determined. Here, we review current studies showing that progressive accumulation of Aβ occurs within the mitochondria of both transgenic mice overexpressing mutant Aβ peptide precursor protein and autopsied brains from AD patients. Interaction of Aβ with Aβ-binding alcohol dehydrogenase (ABAD), a short-chain alcohol dehydrogenase in the mitochondrial matrix, leads to mitochondrial dysfunction evidenced by increased reactive oxygen species generation, mitochondrial membrane permeability formation and caspase-3-like activity induction, and decreased activities of the Krebs cycle. These effects can be blocked by intracellular transduction of the ABAD decoy peptide. We hypothesize that Aβ-induced and mitochondria-dependent cytotoxic pathways might play an important role in AD pathogenesis and could be a potential therapeutic target.

Keywords::

• Alzheimer’s disease
• amyloid-β-binding alcohol dehydrogenase
• amyloid-β peptide
• metabolism
• mitochondria

Financial & competing interests disclosure

This work was supported by grants from the NIH (National Institute on Aging, AG16736, PO1 AG17490 and P50 AG08702), and the Alzheimer’s Association. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.