title: L-3-n-butylphthalide reduces tau phosphorylation and improves cognitive deficits in AβPP/PS1-Alzheimer's transgenic mice.
abstract: L-3-n-butylphthalide (L-NBP), an extract from seeds of Apium graveolens Linn (Chinese celery), has been shown to have neuroprotective effects on cerebral ischemic, vascular dementia and amyloid-β (Aβ)-induced animal models by inhibiting oxidative injury, neuronal apoptosis and glial activation, regulating amyloid-β protein precursor (AβPP) processing and reducing Aβ generation. The aim of the present study was to examine the effect of L-NBP on learning and memory in AβPP and presenilin 1 (PS1) double-transgenic AD mouse model (AβPP/PS1) and the mechanisms of L-NBP in reducing Aβ accumulation and tau phosphorylation. Twelve-month old AβPP/PS1 mice were given 15 mg/kg L-NBP by oral gavage for 3 months. L-NBP treatment significantly improved the spatial learning and memory deficits compared to the vehicle-treated AβPP/PS1 mice, whereas L-NBP treatment had no effect on cerebral Aβ plaque deposition and Aβ levels in brain homogenates. However, we found an L-NBP-induced reduction of tau hyperphosphorylation at Ser199, Thr205, Ser396, and Ser404 sites in AβPP/PS1 mice. Additionally, the expressions of cyclin-dependent kinase and glycogen synthase kinase 3β, the most important kinases involved in tau phosphorylation, were markedly decreased by L-NBP treatment. The effects of L-NBP on decreasing tau phosphorylation and kinases activations were further confirmed in neuroblastoma SK-N-SH cells overexpressing wild-type human AβPP695 (SK-N-SH AβPPwt). L-NBP shows promising candidate of multi-target neuronal protective agent for the treatment of Alzheimer's disease.
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.forename: Yanli
authors.initials: Y
authors.lastname: Hu
authors.forename: Shaofeng
authors.initials: S
authors.lastname: Xu
authors.forename: Pingping
authors.initials: P
authors.lastname: Li
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Lu
authors.forename: Hongyan
authors.initials: H
authors.lastname: Yang
authors.forename: Nan
authors.initials: N
authors.lastname: Feng
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009447:Neuroblastoma / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D053764:Presenilin-1 / Q000235:genetics; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D013037:Spatial Behavior / Q000187:drug effects; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001572:Benzofurans; D018696:Neuroprotective Agents; D053764:Presenilin-1; D016875:tau Proteins; C027125:3-n-butylphthalide; D051360:Cyclin-Dependent Kinase 5; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3