title: Oxidative stress accelerates amyloid deposition and memory impairment in a double-transgenic mouse model of Alzheimer's disease.
abstract: Oxidative stress is known to play a prominent role in the onset and early stage progression of Alzheimer's disease (AD). For example, protein oxidation and lipid peroxidation levels are increased in patients with mild cognitive impairment. Here, we created a double-transgenic mouse model of AD to explore the pathological and behavioral effects of oxidative stress. Double transgenic (APP/DAL) mice were constructed by crossing Tg2576 (APP) mice, which express a mutant form of human amyloid precursor protein (APP), with DAL mice expressing a dominant-negative mutant of mitochondrial aldehyde dehydrogenase 2 (ALDH2), in which oxidative stress is enhanced. Y-maze and object recognition tests were performed at 3 and 6 months of age to evaluate learning and memory. The accumulation of amyloid plaques, deposition of phosphorylated-tau protein, and number of astrocytes in the brain were assessed histopathologically at 3, 6, 9, and 12-15 months of age. The life span of APP/DAL mice was significantly shorter than that of APP or DAL mice. In addition, they showed accelerated amyloid deposition, tau phosphorylation, and gliosis. Furthermore, these mice showed impaired performance on Y-maze and object recognition tests at 3 months of age. These data suggest that oxidative stress accelerates cognitive dysfunction and pathological insults in the brain. APP/DAL mice could be a useful model for exploring new approaches to AD treatment.
authors.affiliation: Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki-city, Kanagawa 211-8533, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kanamaru
authors.affiliation: Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki-city, Kanagawa 211-8533, Japan. Electronic address: nanakash@nms.ac.jp.
authors.forename: Naomi
authors.initials: N
authors.lastname: Kamimura
authors.affiliation: Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki-city, Kanagawa 211-8533, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokota
authors.affiliation: Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki-city, Kanagawa 211-8533, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Iuchi
authors.affiliation: Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki-city, Kanagawa 211-8533, Japan.
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Nishimaki
authors.affiliation: Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Takami
authors.affiliation: Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Akashiba
authors.affiliation: Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Shitaka
authors.affiliation: Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Katsura
authors.affiliation: Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Kimura
authors.affiliation: Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki-city, Kanagawa 211-8533, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ohta
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000523:psychology*; D000682:Amyloid / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism; D005911:Gliosis; D007858:Learning; D008569:Memory Disorders / Q000235:genetics / Q000523:psychology*; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics; D018384:Oxidative Stress; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism
chemical_list: D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D024101:Mitochondrial Proteins; D016875:tau Proteins; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial
keywords: APP transgenic mice; Alzheimer’s disease; Amyloid β; DAL mice; Oxidative stress