A beta and human amylin share a common toxicity pathway via mitochondrial dysfunction

作者：Lim Yun An; Rhein Virginie; Baysang Ginette; Meier Fides; Poljak Anne; Raftery Mark J; Guilhaus Michael; Ittner Lars M; Eckert Anne; Goetz Juergen

来源：Proteomics, 2010, 10(8): 1621-1633.

DOI：10.1002/pmic.200900651

• Alzheimer's disease
• Amyloidosis
• Mitochondrial complex proteins
• Respiration
• Type 2 diabetes mellitus

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are leading causes of morbidity and mortality in the elderly. Both diseases are characterized by amyloid deposition in target tissues: aggregation of amylin in T2DM is associated with loss of insulin-secreting beta-cells, while amyloid beta (A beta) aggregation in AD brain is associated with neuronal loss. Here, we used quantitative iTRAQ proteomics as a discovery tool to show that both All and human amylin (HA) deregulate identical proteins, a quarter of which are mitochondria], supporting the notion that mitochondrial dysfunction is a common target in these two amyloidoses. A functional validation revealed that mitochondrial complex IV activity was significantly reduced after treatment with either HA or A beta, as was mitochondria] respiration. In comparison, complex I activity was reduced only after treatment with HA. A beta and HA, but not the non-amyloidogenic rat amylin, induced significant increases in the generation of ROS. Co-incubation of HA and A beta did not produce an augmented effect in ROS production, again suggesting common toxicity mechanisms. In conclusion, our data suggest that A[3 and HA both exert toxicity, at least in part, via mitochondrial dysfunction, thus restoring their function may be beneficial for both AD and T2DM.

• 出版日期2010-4