Nobiletin, a citrus flavonoid, improves cognitive impairment and reduces soluble Aβ levels in a triple transgenic mouse model of Alzheimer's disease (3XTg-AD).
Alzheimer's disease (AD), the most common form of dementia among the elderly, is characterized by the progressive decline of cognitive function. Increasing evidence indicates that the production and accumulation of amyloid β (Aβ), particularly soluble Aβ oligomers, is central to the pathogenesis of AD. Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from citrus peels, ameliorates learning and memory impairment in olfactory-bulbectomized mice, amyloid precursor protein transgenic mice, NMDA receptor antagonist-treated mice, and senescence-accelerated mouse prone 8. Here, we present evidence that this natural compound improves cognitive impairment and reduces soluble Aβ levels in a triple transgenic mouse model of AD (3XTg-AD) that progressively develops amyloid plaques, neurofibrillary tangles, and cognitive impairments. Treatment with nobiletin (30 mg/kg) for 3 months reversed the impairment of short-term memory and recognition memory in 3XTg-AD mice. Our ELISA analysis also showed that nobiletin reduced the levels of soluble Aβ1-40 in the brain of 3XTg-AD mice. Furthermore, nobiletin reduced ROS levels in the hippocampus of 3XTg-AD as well as wild-type mice. These results suggest that this natural compound has potential to become a novel drug for the treatment and prevention of AD.
Department of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8560, Japan; Department of Drug Safety Sciences, Graduate School of Medicine, Nagoya University, Tsuruma-cho, Showa-ku, Nagoya 466-8560, Japan.
Akira
A
Nakajima
Department of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8560, Japan.
Yuki
Y
Aoyama
Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Japan.
Eun-Joo
EJ
Shin
Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Japan.
Yunsung
Y
Nam
Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Japan.
Hyoung-Chun
HC
Kim
Department of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8560, Japan.
Taku
T
Nagai
Laboratory of Medicinal Plant Science, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo 192-0392, Japan.
Akihito
A
Yokosuka
Laboratory of Medicinal Plant Science, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo 192-0392, Japan.
Yoshihiro
Y
Mimaki
Department of Drug Safety Sciences, Graduate School of Medicine, Nagoya University, Tsuruma-cho, Showa-ku, Nagoya 466-8560, Japan.
Tsuyoshi
T
Yokoi
Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan; Kansei Fukushi Research Institute, Tohoku Fukushi University, Sendai 989-3201, Japan.
Yasushi
Y
Ohizumi
Department of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8560, Japan. Electronic address: kyamada@med.nagoya-u.ac.jp.
Kiyofumi
K
Yamada
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000032:analysis*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004195:Disease Models, Animal; D047309:Flavones / Q000008:administration & dosage*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000032:analysis*; D021641:Recognition, Psychology / Q000187:drug effects
D016229:Amyloid beta-Peptides; D047309:Flavones; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C008661:nobiletin
3XTg-AD; Alzheimer's disease; Memory; Nobiletin; Oxidative stress