Activation of mTOR signaling leads to orthopedic surgery-induced cognitive decline in mice through β-amyloid accumulation and tau phosphorylation

Shen,Wenzhen; Lu,Keliang; Wang,Jiawan; Wu,Anshi; Yue,Yun

doi:10.3892/mmr.2016.5700

Activation of mTOR signaling leads to orthopedic surgery-induced cognitive decline in mice through β-amyloid accumulation and tau phosphorylation

Authors:
- Wenzhen Shen
- Keliang Lu
- Jiawan Wang
- Anshi Wu
- Yun Yue
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Affiliations: Department of Anesthesiology, Beijing Chao‑Yang Hospital, Capital Medical University, Beijing 100020, P.R. China, Department of Anesthesiology, Weifang Medical University, Weifang, Shandong 261031, P.R. China
Published online on: September 1, 2016 https://doi.org/10.3892/mmr.2016.5700
Pages: 3925-3934

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Abstract

Postoperative cognitive dysfunction (POCD) is a serious complication following surgery, however, the mechanism of POCD remains to be elucidated. Previous evidence has revealed that POCD may be associated with the pathogenesis of neurodegenerative processes. The mammalian target of rapamycin (mTOR) signaling pathway has been reported to be crucial in the pathophysiology of neurodegenerative diseases. However, the implications of mTOR in POCD remains to be fully elucidated. In the present study, western blotting and enzyme‑linked immunosorbent assay were used to determine the expression of mTOR and any associated downstream targets; contextual fear conditioning was used to estimate the learning and memory ability of mice. Using an animal model of orthopedic surgery, it was found that surgical injury impaired hippocampal‑dependent memory and enhanced the levels of phosphorylated mTOR at Serine‑2448, phosphorylated 70‑kDa ribosomal protein S6 kinase (p70S6K) at Threonine‑389 with accumulation of β‑amyloid (Aβ) and hyperphosphorylated tau at Serine-396, compared with the control group. Pretreatment with rapamycin, an mTOR inhibitor, restored the abnormal mTOR/p70S6K signaling induced by surgery, attenuated the accumulation of Aβ and reduced the phosphorylation of tau protein. Rapamycin also reversed the surgery‑induced cognitive dysfunction. The results of the present study suggested that the surgical stimulus activated mTOR/p70S6K signaling excessively, and that the inhibition of mTOR signaling with rapamycin may prevent postoperative cognitive deficits, partly through attenuating the accumulation of Aβ and hyperphosphorylation of tau protein.

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