Potassium 2-(1-hydroxypentyl)-benzoate improves memory deficits and attenuates amyloid and tau pathologies in a mouse model of Alzheimer’s disease

WT human APP 695 ; SAMP8, senescence-accelerated mouse prone 8; PKB, protein kinase B; ADAM, A member of the disintegrin and metalloprotease; IHC, Immunohistochemistry. This article has not been copyedited and formatted. The final version may differ from this version. ABSTRACT Alzheimer' disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition and neurofibrillary tangles (NFT). Potassium 2-(1-hydroxypentyl)-benzoate (dl-PHPB), has been shown to have neuroprotective effects on cerebral ischemic, vascular dementia and Aß-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 model (APP/PS1) and the mechanisms of dl-PHPB in reducing Aß accumulation and tau 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 to the vehicle-treated APP/PS1 mice. In the meantime, dl-PHPB obviously reduced tau hyperphosphorylation at Ser199, Thr205 and Ser396 sites and slightly resition and in APP/PS1 mice. This was accompanied by APP phosphorylation reduction and protein kinase C (PKC) activation. In addition, the expressions of cyclin-dependent kinase (CDK-5) and glycogen synthase kinase 3β (GSK-3β), the most important kinases involved in tau phosphorylation, were markedly decreased by dl-PHPB treatment. Phosphorylated Akt and phosphoinositide 3 kinase (PI3K) levels of APP/PS1 mice were significantly reduced compared to wild-type mice, and dl-PHPB reversed the reduction. The effects of dl-PHPB on decreasing tau phosphorylation and kinases activations were further confirmed in neuroblastoma SK-N-SH cells over-expressing WT human APP 695 (SK-N-SH APPwt). These data raised the possibility that dl-PHPB might be a promising multi-target neuronal protective This article has not been copyedited and formatted. The final version may differ from this version.