Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress.
A new gene, termed klotho, is associated with the suppression of several aging phenotypes. Because high expression of klotho gene was detected in the brain, it would be plausible that klotho gene is involved in the regulation of brain aging. We investigated the changes in mnemonic function accompanying aging in klotho mutant mice. Cognitive function measured by novel-object recognition and conditioned-fear tests in klotho mutant mice was normal at the age of 6 wk, but markedly impaired at the age of 7 wk. Lipid (malondialdehyde) and DNA (8-hydroxy-2'-deoxyguanosine) peroxide levels in the hippocampus of klotho mutant mice increased at the age of 5 wk, 2 wk before the development of cognition deficits. Pro-death Bax increased, whereas anti-death Bcl-2 and Bcl-XL decreased, and apoptotic TUNEL-positive cells were detected in the hippocampus of klotho mutant mice at the age of 7 wk. A potent antioxidant, a-tocopherol, prevented cognition impairment and lipid peroxide accumulation and decreased the number of apoptotic cells in klotho mutant mice. These results suggest that oxidative stress has a crucial role in the aging-associated cognition impairment in klotho mutant mice. Klotho protein may be involved in the regulation of antioxidative defense.
Nagai
Taku
T
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
Yamada
Kiyofumi
K
Kim
Hyoung-Chun
HC
Kim
Yong-Sun
YS
Noda
Yukihiro
Y
Imura
Akihiro
A
Nabeshima
Yo-ichi
Y
Nabeshima
Toshitaka
T
D000375:Aging; D000818:Animals; D001921:Brain / Q000378:metabolism; D003071:Cognition; D004249:DNA Damage; D005966:Glucuronidase; D000090265:Klotho Proteins; D008054:Lipid Peroxides / Q000032:analysis; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D008568:Memory / Q000187:drug effects; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009154:Mutation; D018384:Oxidative Stress; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects; D024502:alpha-Tocopherol / Q000494:pharmacology; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D008054:Lipid Peroxides; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D005966:Glucuronidase; D000090265:Klotho Proteins; D024502:alpha-Tocopherol