TY - JOUR
T1 - 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
AU - Esposito, Luke
AU - Raber, Jacob
AU - Kekonius, Lisa
AU - Yan, Fengrong
AU - Yu, Giu Qiu
AU - Bien-Ly, Nga
AU - Puoliväli, Jukka
AU - Scearce-Levie, Kimberly
AU - Masliah, Eliezer
AU - Mucke, Lennart
PY - 2006
Y1 - 2006
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Amyloid precursor protein
KW - Behavior
KW - Mitochondria
KW - Superoxide dismutase-2
KW - Transgenic mice
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U2 - 10.1523/JNEUROSCI.0482-06.2006
DO - 10.1523/JNEUROSCI.0482-06.2006
M3 - Article
C2 - 16687508
AN - SCOPUS:33646922865
SN - 0270-6474
VL - 26
SP - 5167
EP - 5179
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 19
ER -