Aβ and human amylin share a common toxicity pathway via mitochondrial dysfunction

被引:114
作者
Lim, Yun-An [1 ]
Rhein, Virginie [2 ]
Baysang, Ginette [2 ]
Meier, Fides [2 ]
Poljak, Anne [3 ,4 ]
Raftery, Mark J. [3 ]
Guilhaus, Michael [3 ]
Ittner, Lars M. [1 ]
Eckert, Anne [2 ]
Goetz, Juergen [1 ]
机构
[1] Univ Sydney, Brain & Mind Res Inst, Alzheimers & Parkinsons Dis Lab, Camperdown, NSW 2050, Australia
[2] Psychiat Univ Clin Basel, Neurobiol Lab, Basel, Switzerland
[3] Univ New S Wales, Bioanalyt Mass Spectrometry Facil, Sydney, NSW, Australia
[4] Univ New S Wales, Sch Med Sci, Sydney, NSW, Australia
基金
澳大利亚国家健康与医学研究理事会; 瑞士国家科学基金会;
关键词
Alzheimer's disease; Amyloidosis; Mitochondrial complex proteins; Respiration; Type 2 diabetes mellitus; TAU TRANSGENIC MICE; AMYLOID PRECURSOR PROTEIN; P301 L TAU; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; ANIMAL-MODELS; FUNCTIONAL GENOMICS; DIABETES-MELLITUS; CELL APOPTOSIS; OLIGOMERS;
D O I
10.1002/pmic.200900651
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1621 / 1633
页数:13
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