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

Luke Esposito, Jacob Raber, Lisa Kekonius, Fengrong Yan, Giu Qiu Yu, Nga Bien-Ly, Jukka Puoliväli, Kimberly Scearce-Levie, Eliezer Masliah, Lennart Mucke

Research output: Contribution to journalArticlepeer-review

160 Scopus citations

Abstract

Alzheimer's disease (AD) is associated with accumulations of amyloid-β(Aβ) 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 ∼50% of that in Sod2 wild-type (Sod2+/+) mice. A reduction in Sod2 activity did not obviously impair mice without hAPP/Aβ 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/Aβ-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 κB. These results suggest that Sod2 protects the aging brain against hAPP/Aβ-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.

Original languageEnglish (US)
Pages (from-to)5167-5179
Number of pages13
JournalJournal of Neuroscience
Volume26
Issue number19
DOIs
StatePublished - 2006

Keywords

  • Alzheimer's disease
  • Amyloid precursor protein
  • Behavior
  • Mitochondria
  • Superoxide dismutase-2
  • Transgenic mice

ASJC Scopus subject areas

  • Neuroscience(all)

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