Mitochondria-Specific Accumulation of Amyloid [beta] Induces Mitochondrial Dysfunction Leading to Apoptotic Cell Death

• Published in: PloS one 2012-04, Vol.7 (4), p.e34929
• Main Authors: Cha, Moon-Yong, Han, Sun-Ho, Son, Sung Min, Hong, Hyun-Seok, Choi, Young-Ju, Byun, Jayoung, Mook-Jung, Inhee
• Format: Article
• Language: English
• Subjects: Advertising executives; Alzheimer's disease; Apoptosis; Biochemistry; Development and progression; Neurons
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0034929

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].sub.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].sub.1-42 -mediated mitochondrial dysfunction. Furthermore, the mitochondria-targeted accumulation of A[beta].sub.1-42 in HT22 cells using A[beta].sub.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].sub.1-42 -treated HT22 cells. In addition, subsequent mitochondrial dysfunctions were demonstrated in the mitochondria-specific A[beta].sub.1-42 accumulation model, which proved indistinguishable from the mitochondrial impairment induced by exogenous A[beta].sub.1-42 -treated HT22 cells. Finally, cellular toxicity was directly induced by mitochondria-targeted A[beta].sub.1-42 accumulation, which mimics the apoptosis process in exogenous A[beta].sub.1-42 -treated HT22 cells. Taken together, these results indicate that mitochondria-targeted A[beta].sub.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.