Amyloid-beta-induced mitochondrial dysfunction

Abstract

As an important molecule in the pathogenesis of Alzheimer's disease (AD), amyloid-beta (Abeta) interferes with multiple aspects of mitochondrial function, including energy metabolism failure, production of reactive oxygen species (ROS) and permeability transition pore formation. Recent studies have demonstrated that Abeta progressively accumulates within mitochondrial matrix, providing a direct link to mitochondrial toxicity. Abeta-binding alcohol dehydrogenase (ABAD) is localized to the mitochondrial matrix and binds to mitochondrial Abeta. Interaction of ABAD with Abeta exaggerates Abeta-mediated mitochondrial and neuronal perturbation, leading to impaired synaptic function, and dysfunctional spatial learning/memory. Thus, blockade of ABAD/Abeta interaction may be a potential therapeutic strategy for AD.

Fig. 1

Expression of ABAD in transgenic mutant AβPP (Tg mAPP) mice. Analysis of ABAD antigen in various brain regions by ELISA in Tg mAPP mice vs. non-transgenic (NonTg) littermates is shown in panel A. The micrographs demonstrate immunostaining of ABAD in cerebral cortex of Tg mAPP mouse (B) and NonTg control (C).

Fig. 2

Schematic diagram of intramitochondrial trafficking of Aβ and the consequences of interactions between Aβ and ABAD. I, III, IV, V and F₀ denote respiratory chain complexes at mitochondrial inner membrane; + denotes enhancing effect and – denotes inhibitory effect.