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The Journal of Neuroscience, June 11, 2008, 28(24):6239-6249; doi:10.1523/JNEUROSCI.4956-07.2008

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Neurobiology of Disease
Age-Dependent Neurodegeneration Accompanying Memory Loss in Transgenic Mice Defective in Mitochondrial Aldehyde Dehydrogenase 2 Activity

Ikuroh Ohsawa,^1,2 Kiyomi Nishimaki,¹ Yayoi Murakami,¹ Yuko Suzuki,¹ Masahiro Ishikawa,¹ and Shigeo Ohta¹

¹Department of Biochemistry and Cell Biology and ²The Center of Molecular Hydrogen Medicine, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, Kawasaki 211-8533, Japan

Correspondence should be addressed to Shigeo Ohta, Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, 1-396 Kosugi-cho, Nakahra-ku, Kawasaki 211-8533, Japan. Email: ohta{at}nms.ac.jp

Oxidative stress may underlie age-dependent memory loss and cognitive decline. Toxic aldehydes, including 4-hydroxy-2-nonenal (HNE), an end product of lipid peroxides, are known to accumulate in the brain in neurodegenerative disease. We have previously shown that mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies HNE by oxidizing its aldehyde group. To investigate the role of such toxic aldehydes, we produced transgenic mice, which expressed a dominant-negative form of ALDH2 in the brain. The mice had decreased ability to detoxify HNE in their cortical neurons and accelerated accumulation of HNE in the brain. Consequently, their lifespan was shortened and age-dependent neurodegeneration and hyperphosphorylation of tau were observed. Object recognition and Morris water maze tests revealed that the onset of cognitive impairment correlated with the degeneration, which was further accelerated by APOE (apolipoprotein E) knock-out; therefore, the accumulation of toxic aldehydes is by itself critical in the progression of neurodegenerative disease, which could be suppressed by ALDH2.

Key words: ALDH2; HNE; memory loss; mitochondria; oxidative stress; transgenic mice

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Received Nov. 5, 2007; revised May 2, 2008; accepted May 4, 2008.

Correspondence should be addressed to Shigeo Ohta, Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, 1-396 Kosugi-cho, Nakahra-ku, Kawasaki 211-8533, Japan. Email: ohta{at}nms.ac.jp

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