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: Ying Peng, Yanli Hu, Shaofeng Xu, Xianfang Rong, Jiang Li, PingPing Li, Ling Wang, Jinghua Yang, Xiaoliang Wang
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 350 Issue 2 Pg. 361-74 (Aug 2014) ISSN: 1521-0103 [Electronic] United States
• PMID: 24893984 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• 2-(1-hydroxypentyl)-benzoate
• Amyloid beta-Peptides
• Benzoates
• Pentanes
• tau Proteins
• Phosphatidylinositol 3-Kinases
• Cyclin-Dependent Kinase 5
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Proto-Oncogene Proteins c-akt
• Protein Kinase C
• Glycogen Synthase Kinase 3

Topics

• Alzheimer Disease (drug therapy, pathology)
• Amyloid beta-Peptides (metabolism)
• Animals
• Benzoates (therapeutic use)
• Cells, Cultured
• Cyclin-Dependent Kinase 5 (metabolism)
• Disease Models, Animal
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Memory Disorders (drug therapy)
• Mice
• Neuroglia (drug effects)
• Pentanes (therapeutic use)
• Phosphatidylinositol 3-Kinases (physiology)
• Phosphorylation
• Protein Kinase C (physiology)
• Proto-Oncogene Proteins c-akt (physiology)
• tau Proteins (metabolism)