Mitochondria-Specific Accumulation of Amyloid β Induces Mitochondrial Dysfunction Leading to Apoptotic Cell Death

Mitochondria are best known as the essential intracellular organelles that host the homeostasis required for cellular survival, but they also have relevance in diverse disease-related conditions, including Alzheimer's disease (AD). Amyloid beta (A beta) peptide is the key molecule in AD pathogenesis, and has been highlighted in the implication of mitochondrial abnormality during the disease progress. Neuronal exposure to A beta impairs mitochondrial dynamics and function. Furthermore, mitochondrial A beta accumulation has been detected in the AD brain. However, the underlying mechanism of how A beta affects mitochondrial function remains uncertain, and it is questionable whether mitochondrial A beta accumulation followed by mitochondrial dysfunction leads directly to neuronal toxicity. This study demonstrated that an exogenous A beta(1-42) treatment, when applied to the hippocampal cell line of mice (specifically HT22 cells), caused a deleterious alteration in mitochondria in both morphology and function. A clathrin-mediated endocytosis blocker rescued the exogenous A beta(1-42)-mediated mitochondrial dysfunction. Furthermore, the mitochondria-targeted accumulation of A beta(1-42) in HT22 cells using A beta(1-42) with a mitochondria-targeting sequence induced the identical morphological alteration of mitochondria as that observed in the APP/PS AD mouse model and exogenous A beta(1-42)-treated HT22 cells. In addition, subsequent mitochondrial dysfunctions were demonstrated in the mitochondria-specific A beta(1-42) accumulation model, which proved indistinguishable from the mitochondrial impairment induced by exogenous A beta(1-42)-treated HT22 cells. Finally, cellular toxicity was directly induced by mitochondria-targeted A beta(1-42) accumulation, which mimics the apoptosis process in exogenous A beta(1-42)-treated HT22 cells. Taken together, these results indicate that mitochondria-targeted A beta(1-42) accumulation is the necessary and sufficient condition for A beta-mediated mitochondria impairments, and leads directly to cellular death rather than along with other A beta-mediated signaling alterations.