FLZ Alleviates the Memory Deficits in Transgenic Mouse Model of Alzheimer’s Disease via Decreasing Beta-Amyloid Production and Tau Hyperphosphorylation

Xiu-Qi Bao,Hua Sun,Xiang-Chen Kong,Tao Wang,Ning Li,Dan Zhang,Wen-Jiao Tai,Cheng-Xin Gong

doi:10.1371/journal.pone.0078033

Xiu-Qi Bao, Hua Sun + Show 6 more

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https://doi.org/10.1371/journal.pone.0078033

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Abstract

Alzheimer’s disease (AD) is the most common cause of dementia worldwide and mainly characterized by the aggregated β-amyloid (Aβ) and hyperphosphorylated tau. FLZ is a novel synthetic derivative of natural squamosamide and has been proved to improve memory deficits in dementia animal models. In this study, we aimed to investigate the mechanisms of FLZ’s neuroprotective effect in APP/PS1 double transgenic mice and SH-SY5Y (APPwt/swe) cells. The results showed that treatment with FLZ significantly improved the memory deficits of APP/PS1 transgenic mice and decreased apoptosis of SH-SY5Y (APPwt/swe) cells. FLZ markedly attenuated Aβ accumulation and tau phosphorylation both in vivo and in vitro. Mechanistic study showed that FLZ interfered APP processing, i.e., FLZ decreased β-amyloid precursor protein (APP) phosphorylation, APP-carboxy-terminal fragment (APP-CTF) production and β-amyloid precursor protein cleaving enzyme 1 (BACE1) expression. These results indicated that FLZ reduced Aβ production through inhibiting amyloidogenic pathway. The mechanistic study about FLZ’s inhibitory effect on tau phosphorylation revealed t the involvement of Akt/glycogen synthase kinase 3β (GSK3β) pathway. FLZ treatment increased Akt activity and inhibited GSK3β activity both in vivo and in vitro. The inhibitory effect of FLZ on GSK3β activity and tau phosphorylation was suppressed by inhibiting Akt activity, indicating that Akt/GSK3β pathway might be the possible mechanism involved in the inhibitory effect of FLZ on tau hyperphosphorylation. These results suggested FLZ might be a potential anti-AD drug as it not only reduced Aβ production via inhibition amyloidogenic APP processing pathway, but also attenuated tau hyperphosphoylation mediated by Akt/GSK3β.

Highlights

Alzheimer’s disease (AD) is the most common cause of dementia worldwide
The number of amyloid precursor protein (APP)/ PS1 mice crossing the platform and the time spent in the target quadrant remarkably decreased compared with WT mice, and the travel distances were much longer than those of WT mice
Our present finding indicated that FLZ treatment significantly improved memory deficits of APP/PS1 transgenic mice and reduced apoptosis of SH-SY5Y (APPwt/swe) cells

Summary

Introduction

The hallmarks of AD are mainly characterized by senile plaques (SPs) and neurofibrillary tangles (NFTs), which consist of aggregated b-amyloid protein (Ab) and hyperphosphorylated tau protein (p-tau). Ab peptides are generated by successive proteolysis of b-amyloid precursor protein (APP), a large transmembrane glycoprotein, which is initially cleaved by the bamyloid precursor protein cleaving enzyme 1 (BACE1) and subsequently by c-secretase in the transmembrane domain [1]. Aggregated Ab plays a pivotal role in the pathogenesis of AD [2]. Ab aggregates and destroys cell membrane [3], inducing neuronal loss and memory deficits [4,5]. Ab alters cellular metabolism and triggers downstream tau hyperphosphorylation/tangle formation, which plays a major role in the onset of cognitive decline and tau pathology. Aberrant hyperphosphorylated tau is reported to lose its ability to bind and stabilize microtubules, resulting in destabilization of the cytoskeleton and perturbation of axonal transport [6]

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