Amyloid-beta interaction with mitochondria

Abstract

Mitochondrial dysfunction is a hallmark of amyloid-beta(A)-induced neuronal toxicity in Alzheimer's disease (AD). The recent emphasis on the intracellular biology of A and its precursor protein (APP) has led researchers to consider the possibility that mitochondria-associated and/or intramitochondrial A may directly cause neurotoxicity. In this paper, we will outline current knowledge of the intracellular localization of both A and APP addressing the question of how A can access mitochondria. Moreover, we summarize evidence from AD postmortem brain as well as cellular and animal AD models showing that A triggers mitochondrial dysfunction through a number of pathways such as impairment of oxidative phosphorylation, elevation of reactive oxygen species (ROS) production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. In particular, we focus on A interaction with different mitochondrial targets including the outer mitochondrial membrane, intermembrane space, inner mitochondrial membrane, and the matrix. Thus, this paper establishes a modified model of the Alzheimer cascade mitochondrial hypothesis. Copyright © 2011 Lucia Pagani and Anne Eckert.