SOD1 Loss Accelerates Aß Oligomerization and Memory Impairment in Tg2576 Mice
Alzheimer's & Dementia(2012)
Abstract
Oxidative stress is linked to the pathogenesis of neurodegeneration. 1) Beta-amyloid oligomers cause cognitive dysfunction and synaptotoxicity in AD. However, the relationship between oxidative stress, oligomer, and their localization during AD progression is not fully understood. Our group previously reported that mice deficient in cytoplasmic superoxide dismutase (CuZn-SOD, SOD1) have typical phenotypes of geriatric diseases, such as drusen in age-related macular degeneration, fatty liver, skin thinning and osteoporosis. 2) On the other hand, even though mitochondrial oxidative stress has been hitherto believed to be the main contributors to AD, the recent report revealed that mitochondrial SOD (Mn-SOD, SOD2) did not affect Aβ oligomerization in vivo. 3) To evaluate the potential of cytoplasmic oxidative stress in AD, we generated an AD-model mouse lacking Sod 1 (h APP/Sod1 -/-), and analyzed it for AD-like pathology. Memory and behavioral abnormalities were estimated by Morris water maze and Y-maze. Aβ oligomerization was tested on dot blotting and Western blotting. Senile plaque and neuroinflammation were evaluated using immunohistochemistry. The levels of tau, synaptophysin, each SOD were examined by Western blotting. hAPP processing was estimated on ELISA. These findings suggest that cytoplasmic oxidative stress could be involved in Aβ aggregation (oligomerization), as well as production, and imply the role of intracellular Aβ oligomerization. Activation of Sod1 may be a therapeutic strategy to delay AD progression. References: Murakami, K. et al., J. Amino Acids 2011, ID654207. Shimizu, T. et al., Geriatr. Gerontol. Int.2010, 10, S70-S79. Dumont, M. et al., FASEB J.2009, 23, 2459–2466. Murakami, K. et al., J. Biol. Chem. 2011, 286, 44557–44568.Murakami, K. et al., Biosci. Biotechnol. Biochem., in revision.
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Key words
Aß Oligomers,Oxidative Stress,Neurodegeneration
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