Massaad CA, Washington TM, Pautler RG, Klann E.
Overexpression of SOD-2 reduces hippocampal superoxide and prevents memory deficits in a mouse model of Alzheimer's disease.
Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13576-81.
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Strengthening the Links Between Amyloid-β, Mitochondria and Oxidative Stress
Striking features of Alzheimer disease pathophysiology are amyloid-β deposits, reduced brain metabolism, oxidative stress, and cognitive decline. The links between these features are strengthened by the Massaad study. They show that reduction of mitochondrial oxidative stress through overexpression of SOD-2 in a mouse model of Aβ overproduction results not in a reduction in total Aβ, but an alteration in the 40/42 ratio, so that less Aβ is deposited. Further, they show SOD-2 expression improves memory in these mice. These findings support the view that Aβ’s response to oxidative stress has important adaptive features.
Massaad et al. demonstrate it is not just that Aβ is a source for reactive oxygen, or that the enzymes that control Aβ production touch oxidative balance, but rather that almost every critical feature of the cell controls the Aβ system and response to it. Stress in oxidative balance is no error on nature’s part; this critical feature of cellular protection has been adapted, modulated, and finely honed to one of the most intricate networks in the body. Aβ may be one of the critical find modulators of oxidative balance.
This paper shows the beneficial effects of SOD-2 overexpression in transgenic Alzheimer mice. Massaad and colleagues’ data confirmed our previous findings showing that in transgenic Alzheimer mice, overexpression of SOD-2 reduces oxidative stress and amyloid deposition, and improves memory impairments (Dumont et al., 2009).
The mechanism of these effects still remains unclear. In both our and Massaad’s work, the SDS-soluble or formic acid (FA)-soluble pools of Aβ1-42 and Aβ1-40 remained unchanged. Moreover, we also demonstrated that levels of β and α C-terminal fragments of APP were unaffected by SOD-2 overexpression. An interesting outcome of the paper of Massaad is the decrease of Aβ42/40 ratio in the FA-soluble fraction, suggesting a reduction of the most pathogenic isoform of Aβ.
Our study and that of Massaad provide strong evidence that the mitochondrial antioxidant system plays an important role in Alzheimer disease pathogenesis. This is consistent with other evidence that mitochondrial dysfunction and oxidative damage play an important role in AD.
Dumont M, Wille E, Stack C, Calingasan NY, Beal MF, Lin MT.
Reduction of oxidative stress, amyloid deposition, and memory deficit by manganese superoxide dismutase overexpression in a transgenic mouse model of Alzheimer's disease.
FASEB J. 2009 Aug;23(8):2459-66.