Mitochondrial Aβ: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease

TLDR

Amyloid‑beta peptide is implicated in Alzheimer’s disease pathogenesis, yet the mechanisms by which intracellular Abeta impairs neuronal function remain unclear. The study aims to delineate a new mechanism by which Abeta impairs neuronal energetics, contributing to cellular dysfunction in AD. The authors demonstrate that intracellular Abeta accumulates in mitochondria, reducing respiratory chain complex III and IV activity and oxygen consumption. In transgenic mice and AD patients, mitochondrial Abeta, especially Abeta42, progressively accumulates and impairs respiratory chain activity, with detectable levels as early as 4 months before extracellular deposits.

Abstract

Although amyloid-beta peptide (Abeta) is the neurotoxic species implicated in the pathogenesis of Alzheimer's disease (AD), mechanisms through which intracellular Abeta impairs cellular properties, resulting in neuronal dysfunction, remain to be clarified. Here we demonstrate that intracellular Abeta is present in mitochondria from brains of transgenic mice with targeted neuronal overexpression of mutant human amyloid precursor protein and AD patients. Abeta progressively accumulates in mitochondria and is associated with diminished enzymatic activity of respiratory chain complexes (III and IV) and a reduction in the rate of oxygen consumption. Importantly, mitochondria-associated Abeta, principally Abeta42, was detected as early as 4 months, before extensive extracellular Abeta deposits. Our studies delineate a new means through which Abeta potentially impairs neuronal energetics, contributing to cellular dysfunction in AD.