Amyloid-Beta interaction with mitochondria.

Mitochondrial dysfunction is a hallmark of amyloid-beta(Aβ)-induced neuronal toxicity in Alzheimer's disease (AD). The recent emphasis on the intracellular biology of Aβ and its precursor protein (AβPP) has led researchers to consider the possibility that mitochondria-associated and/or intramitochondrial Aβ may directly cause neurotoxicity. In this paper, we will outline current knowledge of the intracellular localization of both Aβ and AβPP addressing the question of how Aβ can access mitochondria. Moreover, we summarize evidence from AD postmortem brain as well as cellular and animal AD models showing that Aβ 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 Aβ 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.