Mitochondrial dysfunction and axonal degeneration are early pathological features of Alzheimer's disease (AD)-affected brains. The underlying mechanisms and strategies to rescue it have not been well elucidated. Here, we evaluated axonal mitochondrial transport and function in AD subject-derived mitochondria. We analyzed mitochondrial transport and kinetics in human trans-mitochondrial "cybrid" (cytoplasmic hybrid) neuronal cells whose mitochondria were derived from platelets of patients with sporadic AD and compared these AD cybrid cell lines with cybrid cell lines whose mitochondria were derived from age-matched, cognitively normal subjects. Human AD cybrid cell lines, when induced to differentiate, developed stunted projections. Mitochondrial transport and function within neuronal processes/axons was altered in AD-derived mitochondria. Antioxidants reversed deficits in axonal mitochondrial transport and function. These findings suggest that antioxidants may be able to mitigate the consequences of AD-associated mitochondrial dysfunction. The present study provides evidence of the cause/effect of AD specific mitochondrial defects, which significantly enhances our understanding of the AD pathogenesis and exploring the effective therapeutic strategy for AD.
Keywords: Alzheimer’s disease; antioxidants; cybrid cells; mitochondrial dysfunction; mitochondrial transport.