Nobiletin, a citrus flavonoid, improves memory impairment and Abeta pathology in a transgenic mouse model of Alzheimer's disease.
Increasing evidence suggests that the elevation of beta-amyloid (Abeta) peptides in the brain is central to the pathogenesis of Alzheimer's disease (AD). Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from citrus peels, enhances cAMP/protein kinase A/extracellular signal-regulated kinase/cAMP response element-binding protein signaling in cultured hippocampal neurons and ameliorates Abeta-induced memory impairment in AD model rats. For the first time, we report that this natural compound improves memory deficits in amyloid precursor protein (APP) transgenic mice that overexpress human APP695 harboring the double Swedish and London mutations [APP-SL 7-5 transgenic (Tg) mice]. Our enzyme-linked immunosorbent assay (ELISA) also showed that administration of nobiletin to the transgenic mice for 4 months markedly reduced quantity of guanidine-soluble Abeta(1-40) and Abeta(1-42) in the brain. Furthermore, consistent with the results of ELISA, by immunohistochemistry with anti-Abeta antibody, it was evidently shown that the administration of nobiletin decreased the Abeta burden and plaques in the hippocampus of APP-SL 7-5 Tg mice. These findings suggest that this natural compound has potential to become a novel drug for fundamental treatment of AD.
Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
Hiroshi
H
Onozuka
Akira
A
Nakajima
Kentaro
K
Matsuzaki
Ryong-Woon
RW
Shin
Koichi
K
Ogino
Daisuke
D
Saigusa
Naomi
N
Tetsu
Akihito
A
Yokosuka
Yutaka
Y
Sashida
Yoshihiro
Y
Mimaki
Tohru
T
Yamakuni
Yasushi
Y
Ohizumi
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002957:Citrus; D004195:Disease Models, Animal; D047309:Flavones / Q000737:chemistry / Q000627:therapeutic use*; D005419:Flavonoids / Q000737:chemistry / Q000627:therapeutic use*; D008569:Memory Disorders / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
D016229:Amyloid beta-Peptides; D047309:Flavones; D005419:Flavonoids; C008661:nobiletin