L-3-n-butylphthalide Reduces Tau Phosphorylation and Improves Cognitive Deficits in AβPP/PS1-Alzheimer's Transgenic Mice

Article type: Research Article

Authors: Peng, Ying^{a; 1} | Hu, Yanli^{a; b; 1} | Xu, Shaofeng^a | Li, Pingping^a | Li, Jiang^a | Lu, Li^a | Yang, Hongyan^a | Feng, Nan^a | Wang, Ling^a | Wang, Xiaoliang^{a; *}

Affiliations: [a] 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 | [b] Permanent address: College of Pharmaceutical Sciences, Shihezi University, Shihezi, China

Correspondence: [*] Correspondence to: Xiaoliang Wang, Ph.D., Pharmacology Department, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1, Xiannongtan Street, 100050 Beijing, China. Tel.: +86 10 63165173; Fax: +86 10 63165330; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

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.

Keywords: Alzheimer's disease, amyloid-β, CDK-5, GSK-3β, L-3-n-butylphthalide, tau

DOI: 10.3233/JAD-2011-111577

Journal: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 379-391, 2012