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J Neurosci. 2006 May 10;26(19):5167-79.

Reduction in mitochondrial superoxide dismutase modulates Alzheimer's disease-like pathology and accelerates the onset of behavioral changes in human amyloid precursor protein transgenic mice.

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  • 1Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.

Abstract

Alzheimer's disease (AD) is associated with accumulations of amyloid-beta (Abeta) peptides, oxidative damage, mitochondrial dysfunction, neurodegeneration, and dementia. The mitochondrial antioxidant manganese superoxide dismutase-2 (Sod2) might protect against these alterations. To test this hypothesis, we inactivated one Sod2 allele (Sod2(+/-)) in human amyloid precursor protein (hAPP) transgenic mice, reducing Sod2 activity to approximately 50% of that in Sod2 wild-type (Sod2(+/+)) mice. A reduction in Sod2 activity did not obviously impair mice without hAPP/Abeta expression. In hAPP mice, however, it accelerated the onset of behavioral alterations and of deficits in prepulse inhibition of acoustic startle, a measure of sensorimotor gating. In these mice, it also worsened hAPP/Abeta-dependent depletion of microtubule-associated protein 2, a marker of neuronal dendrites. Sod2 reduction decreased amyloid plaques in the brain parenchyma but promoted the development of cerebrovascular amyloidosis, gliosis, and plaque-independent neuritic dystrophy. Sod2 reduction also increased the DNA binding activity of the transcription factor nuclear factor kappaB. These results suggest that Sod2 protects the aging brain against hAPP/Abeta-induced impairments. Whereas reductions in Sod2 would be expected to trigger or exacerbate neuronal and vascular pathology in AD, increasing Sod2 activity might be of therapeutic benefit.

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