New insights in the amyloid-Beta interaction with mitochondria

Abstract

Biochemical and morphological alterations of mitochondria may play an important role in the pathogenesis of Alzheimer's disease (AD). Particularly, mitochondrial dysfunction is a hallmark of amyloid-beta-induced neuronal toxicity in Alzheimer's disease. The recent emphasis on the intracellular biology of amyloid-beta and its precursor protein (APP) has led researchers to consider the possibility that mitochondria-associated and mitochondrial amyloid-beta may directly cause neurotoxicity. Both proteins are known to localize to mitochondrial membranes, block the transport of nuclear-encoded mitochondrial proteins to mitochondria, interact with mitochondrial proteins, disrupt the electron transport chain, increase reactive oxygen species production, cause mitochondrial damage, and prevent neurons from functioning normally. In this paper, we will outline current knowledge of the intracellular localization of amyloid-beta. Moreover, we summarize evidence from AD postmortem brain as well as animal AD models showing that amyloid-beta triggers mitochondrial dysfunction through a number of pathways such as impairment of oxidative phosphorylation, elevation of reactive oxygen species production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. Thus, this paper supports the Alzheimer cascade mitochondrial hypothesis such as the most important early events in this disease, and probably one of the future strategies on the therapy of this neurodegenerative disease.

Figure 1

Representative electromicrographs of mitochondrial ultrastructure. Scale bar 200 nm.

Figure 2

APP processing in nondemented healthy individuals and AD patients. APP processing occurs by two pathways: a beta-secretase-based amyloidogenic and alpha-secretase-based nonamyloidogenic pathway. In the nonamyloidogenic pathway (left), cleavage occurs by alpha-secretase within the amyloid-beta domain and generates the large soluble N-terminal fragment (sAPPα) and a non-amyloidogenic C-terminal fragment of 83 amino acid residues (C83). Further cleavage of this C-terminal fragment by γ-secretase generates the nonamyloidogenic peptide (P3) and APP intracellular domain (ACID). These products are nontoxic. The non-amyloidogenic α-secretase pathway occurs in over 90% of humans, and these individuals generally do not develop dementia. In the amyloidogenic pathway (right), cleavage occurs by β-secretase at the beginning of the amyloid-beta domain and generates a soluble N-terminus fragment (sAPPβ) and amyloidogenic C-terminal fragment of 99 residues (C99). This C-terminal fragment is further cleaved by γ-secretase and generates amyloid-beta. The amyloidogenic pathway occurs in approximately 10% of total humans, and these individuals might develop dementia and AD.