title: Potassium 2-(1-hydroxypentyl)-benzoate improves memory deficits and attenuates amyloid and τ pathologies in a mouse model of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition and neurofibrillary tangles. Dl-PHPB [potassium 2-(1-hydroxypentyl)-benzoate], has been shown to have neuroprotective effects on cerebral ischemic, vascular dementia, and Aβ-induced animal models by inhibiting oxidative injury, neuronal apoptosis, and glial activation. The aim of the present study was to examine the effect of dl-PHPB on learning and memory in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic AD mouse models (APP/PS1) and the mechanisms of dl-PHPB in reducing Aβ accumulation and τ phosphorylation. Twelve-month-old APP/PS1 mice were given 30 mg/kg dl-PHPB by oral gavage for 3 months. Dl-PHPB treatment significantly improved the spatial learning and memory deficits compared with the vehicle-treated APP/PS1 mice. In the meantime, dl-PHPB obviously reduced τ hyperphosphorylation at Ser199, Thr205, and Ser396 sites in APP/PS1 mice. This reduction was accompanied by APP phosphorylation reduction and protein kinase C activation. In addition, expression of cyclin-dependent kinase and glycogen synthase kinase 3β, the most important kinases involved in τ phosphorylation, was markedly decreased by dl-PHPB treatment. Phosphorylated protein kinase B and phosphoinositide 3-kinase levels of APP/PS1 mice were significantly reduced compared with levels in wild-type mice, and dl-PHPB reversed the reduction. The effects of dl-PHPB effecting a decrease in τ phosphorylation and kinase activation were further confirmed in neuroblastoma SK-N-SH cells overexpressing wild-type human APP695. These data raised the possibility that dl-PHPB might be a promising multitarget neuronal protective agent for the treatment of AD.
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Shaofeng
authors.initials: S
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Xianfang
authors.initials: X
authors.lastname: Rong
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: PingPing
authors.initials: P
authors.lastname: Li
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China wangxl@imm.ac.cn.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001565:Benzoates / Q000627:therapeutic use*; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008569:Memory Disorders / Q000188:drug therapy*; D051379:Mice; D009457:Neuroglia / Q000187:drug effects; D010420:Pentanes / Q000627:therapeutic use*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C511222:2-(1-hydroxypentyl)-benzoate; D016229:Amyloid beta-Peptides; D001565:Benzoates; D010420:Pentanes; D016875:tau Proteins; D019869:Phosphatidylinositol 3-Kinases; D051360:Cyclin-Dependent Kinase 5; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D038362:Glycogen Synthase Kinase 3