Mitochondrial superoxide: a key player in Alzheimer's disease

Our recent study characterized a role for mitochondrial superoxide in the pathology of Alzheimer’s disease [1]. Using the Tg2576 Alzheimer's disease (AD) mouse model in combination with a mouse that overexpresses the mitochondrial antioxidant enzyme superoxide dismutase (SOD-2), we showed that severe deficits in the spatial and associative memory of AD mice could be prevented by scavenging of superoxide. SOD-2 overexpression also resulted in a reduction in amyloid-β (Aβ) plaque deposition without affecting the levels of soluble and fibrillar Aβ. It did however lead to a reduction in the Aβ 42/40 ratio resulting in an Aβ pool composition less favorable for aggregation. These findings point towards the involvement of mitochondrial superoxide in AD pathology perhaps through its effects on Aβ processing. Here we discuss these findings and comment on the future directions that this research may lead to. Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the neuropathological deposition of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles [2]. The disease also is characterized by the devastating loss of memory and cognitive functions, which is thought to arise from the increased production of Aβ [3]. The neurotoxic role of Aβ has long been established [3], however, it is not clear how it contributes to the cognitive deficits characteristic of AD. In addition to Aβ, several studies have implicated oxidative stress in the etiology of AD. Oxidative stress occurs mainly as a