Age-dependent neurodegeneration accompanying memory loss in transgenic mice defective in mitochondrial aldehyde dehydrogenase 2 activity.
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.
Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, Kawasaki 211-8533, Japan.
Ikuroh
I
Ohsawa
Kiyomi
K
Nishimaki
Yayoi
Y
Murakami
Yuko
Y
Suzuki
Masahiro
M
Ishikawa
Shigeo
S
Ohta
D000375:Aging / Q000502:physiology*; D000444:Aldehyde Dehydrogenase / Q000172:deficiency* / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000447:Aldehydes / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D004622:Embryo, Mammalian; D005106:Exploratory Behavior / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000150:complications* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000150:complications* / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D010364:Pattern Recognition, Visual / Q000502:physiology; D020648:Peptide Elongation Factor 1 / Q000235:genetics; D011597:Psychomotor Performance / Q000502:physiology
D000447:Aldehydes; D009419:Nerve Tissue Proteins; D020648:Peptide Elongation Factor 1; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C027576:4-hydroxy-2-nonenal