Mitochondria-targeted Amyloid: Relevance to Neurotoxicity and Alzheimer’s Disease

Most neurodegenerative diseases, such as Alzheimer’s disease (AD), have been identified as multifactorial diseases characterized by a progressive decline in physiological functions. Impairment of the mitochondrial respiratory chain has been extensively described in relation to AD. It has been reported that the amyloid species Aβ1-42 may be implicated in mitochondrial dysfunction, leading to cell death. Using the SK-N-AS human neuroblastoma cell line, confocal microscopy and immuno-electron microscopy the mitochondrial targeting of exogenous Aβ1-42 was investigated. The type of Aβ1-42 present in the mitochondrial fraction of Aβ1-42-treated neuronal cells was examined by immunoblot analysis. The direct toxic effect of Aβ1-42 on SK-N-AS cells and isolated rat brain mitochondria was investigated. Using human cell lines of various tissue origin and diverse self-aggregating peptides the specificity of the toxic effect Aβ1-42 was evaluated. To further demonstrate the specificity of the phenomena observed, the steroidal caprospinol, a compound shown to bind to A 1-42 and protect neuronal cells against A 142 –induced neurotoxicity was used. When applied on neuronal cells, Aβ1-42 is taken up by the cells and targeted to mitochondria in a time-dependent manner. A 1-42 has deleterious effects on SK-N-AS cells and on isolated rat brain mitochondria in part by directly