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. 2019 Jul;44(1):313-323.
doi: 10.3892/ijmm.2019.4198. Epub 2019 May 15.

Alteration of the Wnt/GSK3β/β‑catenin signalling pathway by rapamycin ameliorates pathology in an Alzheimer's disease model

Jingfei Chen  1 , Zhimin Long  1 , Yanzhen Li  1 , Min Luo  1 , Shifang Luo  1 , Guiqiong He  1
Affiliations

Alteration of the Wnt/GSK3β/β‑catenin signalling pathway by rapamycin ameliorates pathology in an Alzheimer's disease model

Jingfei Chen et al. Int J Mol Med. 2019 Jul.

Abstract

The abnormal activation of glycogen synthase kinase 3β (GSK3β) is one of the mechanisms involved in the pathogenesis of Alzheimer's disease (AD), which results in amyloid β‑peptide (Aβ) plaque overproduction, Tau hyperphosphorylation and neuronal loss. A number of studies have reported that the activation of the mammalian target of rapamycin (mTOR) contributes to the generation and deposition of Aβ, as well as to the formation of neurofibrillary tangles (NFTs) by inhibiting autophagy. GSK3β is also involved in the mTOR signalling pathway. However, whether the inhibition of the activation of mTOR via the regulation of the function of GSK3β affects the pathology of AD remains unclear. In this study, we intraperitoneally injected amyloid precursor protein (APP)/presenilin‑1 (PS1) transgenic mice with rapamycin, a known activator of autophagy that inhibits mTOR. Our results revealed that rapamycin treatment decreased senile plaque deposition by reducing APP generation, and downregulating β‑ and γ‑secretase activity. Rapamycin also increased Aβ clearance by promoting autophagy and reduced Tau hyperphosphorylation by upregulating the levels of insulin‑degrading enzyme. Additionally, rapamycin markedly promoted the proliferation of differentiated SH‑SY5Y cells stably transfected with the APPswe gene and prevented neuronal loss in the brains of mice in a model of AD. Moreover, rapamycin induced autophagy and promoted autolysosome degradation. In this study, we provide evidence that rapamycin inhibits GSK3β activation and elevates β‑catenin expression by improving the Wnt3a expression levels, which facilitates the amelioration of AD pathology. On the whole, our findings indicate that rapamycin inhibits the activation of mTOR and alters the Wnt/GSK3β/β‑catenin signalling pathway; thus, it may serve as a therapeutic target in the treatment of AD.

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