Escitalopram attenuates β-amyloid-induced tau hyperphosphorylation in primary hippocampal neurons through the 5-HT1A receptor mediated Akt/GSK-3β pathway

Xiang Tang,Xiao-Li Li,Lin Xu,Yan-Juan Wang,Wei-Gang Gong,Feng Bai,Fang-Fang Wu,Zhi-Jun Zhang,Qing-Guo Ren,Di Wu

doi:10.18632/oncotarget.7798

Abstract

Tau hyperphosphorylation is an important pathological feature of Alzheimer's disease (AD). To investigate whether escitalopram could inhibit amyloid-β (Aβ)-induced tau hyperphosphorylation and the underlying mechanisms, we treated the rat primary hippocampal neurons with Aβ1-42 and examined the effect of escitalopram on tau hyperphosphorylation. Results showed that escitalopram decreased Aβ1–42-induced tau hyperphosphorylation. In addition, escitalopram activated the Akt/GSK-3β pathway, and the PI3K inhibitor LY294002 blocked the attenuation of tau hyperphosphorylation induced by escitalopram. Moreover, the 5-HT1A receptor agonist 8-OH-DPAT also activated the Akt/GSK-3β pathway and decreased Aβ1-42-induced tau hyperphosphorylation. Furthermore, the 5-HT1A receptor antagonist WAY-100635 blocked the activation of Akt/GSK-3β pathway and the attenuation of tau hyperphosphorylation induced by escitalopram. Finally, escitalopram improved Aβ1–42 induced impairment of neurite outgrowth and spine density, and reversed Aβ1–42 induced reduction of synaptic proteins. Our results demonstrated that escitalopram attenuated Aβ1–42-induced tau hyperphosphorylation in primary hippocampal neurons through the 5-HT1A receptor mediated Akt/GSK-3β pathway.

Highlights

Alzheimer’s disease (AD) is the most common cause of dementia in elderly people
The present study revealed that escitalopram could protect cultured hippocampal neurons against Aβ1-42induced tau hyperphosphorylation through the PI3K/ Akt/glycogen synthase kinase-3β (GSK-3β) pathway, with the involvement of 5-HT1A receptor (5-HT1AR)
Escitalopram may have a potent effect on neurite outgrowth of hippocampal neurons exposed to Aβ protein fragment 1-42 (Aβ1-42)

Summary

Introduction

Neurofibrillary tangles, composed of abnormally hyperphosphorylated tau, are key lesions of AD [1]. Abnormal hyperphosphorylation of tau converts it from a microtubule assemblypromoting to a microtubule-disrupting protein, leading to the destabilization of microtubules, the impairment of axonal transport, the dysfunction of hippocampal synaptic plasticity, and eventually the neuronal death [2]. Animal studies have consistently shown that the abnormal hyperphosphorylation of tau causes cognitive impairment [3, 4]. Postmortem and imaging studies demonstrated that the reduction of 5-HT and 5-HT1A receptor (5-HT1AR) in the hippocampus is correlated with cognitive decline in AD patients [5, 6]. Preclinical studies have demonstrated a favorable cognitive-improving effect of SSRIs [10, 11].

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Conclusion