PMID- 35197970 OWN - NLM STAT- MEDLINE DCOM- 20220322 LR - 20220322 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 13 DP - 2022 TI - Rapamycin Attenuated Zinc-Induced Tau Phosphorylation and Oxidative Stress in Rats: Involvement of Dual mTOR/p70S6K and Nrf2/HO-1 Pathways. PG - 782434 LID - 10.3389/fimmu.2022.782434 [doi] LID - 782434 AB - Alzheimer's disease is pathologically characterized by abnormal accumulation of amyloid-beta plaques, neurofibrillary tangles, oxidative stress, neuroinflammation, and neurodegeneration. Metal dysregulation, including excessive zinc released by presynaptic neurons, plays an important role in tau pathology and oxidase activation. The activities of mammalian target of rapamycin (mTOR)/ribosomal S6 protein kinase (p70S6K) are elevated in the brains of patients with Alzheimer's disease. Zinc induces tau hyperphosphorylation via mTOR/P70S6K activation in vitro. However, the involvement of the mTOR/P70S6K pathway in zinc-induced oxidative stress, tau degeneration, and synaptic and cognitive impairment has not been fully elucidated in vivo. Here, we assessed the effect of pathological zinc concentrations in SH-SY5Y cells by using biochemical assays and immunofluorescence staining. Rats (n = 18, male) were laterally ventricularly injected with zinc, treated with rapamycin (intraperitoneal injection) for 1 week, and assessed using the Morris water maze. Evaluation of oxidative stress, tau phosphorylation, and synaptic impairment was performed using the hippocampal tissue of the rats by biochemical assays and immunofluorescence staining. The results from the Morris water maze showed that the capacity of spatial memory was impaired in zinc-treated rats. Zinc sulfate significantly increased the levels of P-mTOR Ser2448, P-p70S6K Thr389, and P-tau Ser356 and decreased the levels of nuclear factor erythroid 2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1) in SH-SY5Y cells and in zinc-treated rats compared with the control groups. Increased expression of reactive oxygen species was observed in zinc sulfate-induced SH-SY5Y cells and in the hippocampus of zinc-injected rats. Rapamycin, an inhibitor of mTOR, rescued zinc-induced increases in mTOR/p70S6K activation, tau phosphorylation, and oxidative stress, and Nrf2/HO-1 inactivation, cognitive impairment, and synaptic impairment reduced the expression of synapse-related proteins in zinc-injected rats. In conclusion, our findings imply that rapamycin prevents zinc-induced cognitive impairment and protects neurons from tau pathology, oxidative stress, and synaptic impairment by decreasing mTOR/p70S6K hyperactivity and increasing Nrf2/HO-1 activity. CI - Copyright (c) 2022 Lai, Chen, Ding, Chen, Su, Liu, Ni and Tang. FAU - Lai, Chencen AU - Lai C AD - Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang, China. AD - Department of Nosocomial Infection, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China. FAU - Chen, Zhuyi AU - Chen Z AD - Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang, China. FAU - Ding, Yuanting AU - Ding Y AD - Department of Nosocomial Infection, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China. FAU - Chen, Qian AU - Chen Q AD - Department of Nosocomial Infection, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China. FAU - Su, Songbai AU - Su S AD - Department of Nosocomial Infection, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China. FAU - Liu, Heng AU - Liu H AD - Department of Anesthesiology, Tongren Municipal People's Hospital, Tongren, China. FAU - Ni, Ruiqing AU - Ni R AD - Institute for Regenerative Medicine, University of Zurich, Zurich, Switzerland. AD - Institute for Biomedical Engineering, Eidgenossische Technische Hochschule Zurich (ETH) and University of Zurich, Zurich, Switzerland. FAU - Tang, Zhi AU - Tang Z AD - Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220207 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Amyloid beta-Peptides) RN - 0 (NF-E2-Related Factor 2) RN - 0 (NFE2L2 protein, human) RN - 0 (tau Proteins) RN - EC 1.14.14.18 (HMOX1 protein, human) RN - EC 1.14.14.18 (Heme Oxygenase-1) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.1 (ribosomal protein S6 kinase, 70kD, polypeptide 2) RN - J41CSQ7QDS (Zinc) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Amyloid beta-Peptides/metabolism MH - Animals MH - Heme Oxygenase-1/metabolism MH - Humans MH - Male MH - NF-E2-Related Factor 2/metabolism MH - Oxidative Stress/drug effects MH - Phosphorylation/*drug effects MH - Rats MH - Ribosomal Protein S6 Kinases, 70-kDa MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases/metabolism MH - Zinc/metabolism MH - tau Proteins/metabolism PMC - PMC8858937 OTO - NOTNLM OT - animal model OT - Nrf2/HO-1 (nuclear factor erythroid 2-related factor-2/heme oxygenase-1) OT - cognitive deficit OT - mTOR/p70S6K pathway OT - oxidative stress OT - rapamycin OT - tau hyperphosphorylation OT - zinc COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/02/25 06:00 MHDA- 2022/03/23 06:00 PMCR- 2022/01/01 CRDT- 2022/02/24 05:41 PHST- 2021/09/24 00:00 [received] PHST- 2022/01/13 00:00 [accepted] PHST- 2022/02/24 05:41 [entrez] PHST- 2022/02/25 06:00 [pubmed] PHST- 2022/03/23 06:00 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2022.782434 [doi] PST - epublish SO - Front Immunol. 2022 Feb 7;13:782434. doi: 10.3389/fimmu.2022.782434. eCollection 2022.