. 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. PubMed.


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  1. 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.

  2. The findings of Massaad and colleagues will advance our basic understanding of the neuroprotective role of mitochondrially targeted antioxidants in Alzheimer disease (AD) pathogenesis. Their findings suggest that mitochondrial superoxide dismutase 2 (SOD2) decreases hippocampal superoxide radicals, ameliorates learning/memory deficits, and decreases amyloid-β (Aβ) plaques in double transgenic mice that overexpress SOD2 and mutant human amyloid precursor protein. Interestingly, they also found a decreased ratio of Aβ1-42 to 1-40 in double transgenic mice. These findings further support the mitochondrial oxidative damage hypothesis of AD, and may have important implications for mitochondrially targeted antioxidant therapeutics in AD.

    Increasing evidence suggests that mitochondrial abnormalities are involved in the development and progression of AD (reviewed in Reddy, 2009). Further, it has been proposed that mitochondrially generated free radicals and oxidative damage are involved in abnormal processing of APP and in generating Aβ peptide by activating β- and γ-secretases (Reddy, 2006; Reddy and Beal, 2008). There is some evidence to support this hypothesis (Tamagno et al., 2008; Jin et al., 2008). Further, recently several groups (Crouch et al., 2005; Caspersen et al., 2005; Manczak et al., 2006; Devi et al., 2006; Hanson Petersen et al., 2008) found that Aβ peptide is localized to mitochondrial membranes and the mitochondrial matrix, and that mitochondrially localized Aβ peptide interacts with mitochondrial proteins, induces free radical production, decreases cytochrome oxidase activity, inhibits ATP production, and damages AD neurons. In addition, recent structural studies revealed that Aβ fragments mitochondria, suggesting that mitochondrial structural abnormalities (caused by Aβ) may be critical for mitochondrial dysfunction in AD (Wang et al., 2009; Mao et al., 2009). Overall, these studies suggest that Aβ and mitochondrial dysfunction play a big role in AD pathogenesis.

    To determine the role of overexpressed SOD2 in AD pathogenesis, Massaad et al. crossed SOD2 transgenic mice with Tg2576 mice and studied cognitive deficits, Aβ1-42 and 1-40 levels, and Aβ deposits in Tg2576 mice and double mutant mice (SOD2xTg2576 mice). They found decreased Aβ deposits and reduced cognitive deficits in double transgenic mice relative to Tg2576 mice, suggesting that mitochondrial superoxide dismutase improves cognitive functions in AD. However, it is still unclear 1) how overexpressed mitochondrial superoxide dismutase alters the ratio of Aβ1-42 to 1-40; and 2) how overexpressed mitochondrial superoxide dismutase improves learning and memory functions in double mutant mice. Further research is needed to find answers to these questions, and the answers may have some important implications to AD patients.

    Overall, findings of the study by Massaad and colleagues, together with previous studies (Hirai et al., 2001; Swerdlow et al., 1997; Reddy et al., 2004; Manczak et al., 2004; Caspersen et al., 2005; Manczak et al., 2006; Devi et al., 2006; Hansson Petersen et al., 2008; Wang et al., 2009), improve our understanding of mitochondrial oxidative damage in AD pathogenesis. Given the limited success of recent clinical trials using natural antioxidants in AD patients, findings from this new study may have some important implications for the development of mitochondrially targeted therapeutics for AD patients.

    See also:

    Mao P, Manczak M, Shree D and Reddy PH. Abnormal mitochondrial structural and functional changes caused by amyloid beta in Alzheimer’s disease. Paper presented at the International Conference on Alzheimer’s disease held Vienna, Austria July 11-16, 2009.


    . Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease. FASEB J. 2005 Dec;19(14):2040-1. PubMed.

    . Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction. J Neurosci. 2006 Aug 30;26(35):9057-68. PubMed.

    . The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13145-50. PubMed.

    . Mitochondrial abnormalities in Alzheimer's disease. J Neurosci. 2001 May 1;21(9):3017-23. PubMed.

    . DNA damage-inducing agents elicit gamma-secretase activation mediated by oxidative stress. Cell Death Differ. 2008 Sep;15(9):1375-84. PubMed.

    . Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet. 2006 May 1;15(9):1437-49. PubMed.

    . Differential expression of oxidative phosphorylation genes in patients with Alzheimer's disease: implications for early mitochondrial dysfunction and oxidative damage. Neuromolecular Med. 2004;5(2):147-62. PubMed.

    . Amyloid precursor protein-mediated free radicals and oxidative damage: implications for the development and progression of Alzheimer's disease. J Neurochem. 2006 Jan;96(1):1-13. PubMed.

    . Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer's disease. Exp Neurol. 2009 Aug;218(2):286-92. PubMed.

    . Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends Mol Med. 2008 Feb;14(2):45-53. PubMed.

    . Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease. Hum Mol Genet. 2004 Jun 15;13(12):1225-40. PubMed.

    . Cybrids in Alzheimer's disease: a cellular model of the disease?. Neurology. 1997 Oct;49(4):918-25. PubMed.

    . Oxidative stress activates a positive feedback between the gamma- and beta-secretase cleavages of the beta-amyloid precursor protein. J Neurochem. 2008 Feb;104(3):683-95. PubMed.

    . Impaired balance of mitochondrial fission and fusion in Alzheimer's disease. J Neurosci. 2009 Jul 15;29(28):9090-103. PubMed.

    View all comments by Hemachandra Reddy
  3. 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.


    . 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. PubMed.

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