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The neuroprotective effects of SIRT1 in mice carrying the APP/PS1 double-transgenic mutation and in SH-SY5Y cells over-expressing human APP670/671 may involve elevated levels of ?7 nicotinic acetylcholine receptors.

ABSTRACT: The aim was to determine whether the neuroprotective effect of SIRT1 in Alzheimer's disease (AD), due to inhibition of aggregation of the ?-amyloid peptide (A?), involves activation of ?7 nAChR. In present study, four-month-old APP/PS1 mice were administered resveratrol (RSV) or suramin once daily for two months, following which their spatial learning and memory were assessed using the Morris water maze test. Deposits of A? in vivo were detected by near-infrared imaging (NIRI) and confocal laser scanning. SH-SY5Y/APPswe cells were treated with RSV, suramin, U0126 or methyllycaconitine (MLA). Levels of proteins and mRNA were determined by Western blotting and qRT-PCR, respectively. The results show that activation of SIRT1 improved their spatial learning and memory and reduced the production and aggregation of A? in the hippocampus and cerebral cortex; whereas inhibition of SIRT1 had the opposite effects. In addition, activation of SIRT1 increased the levels of both ?7 nAChR and ?APP in the brains these animals. Finally, activation of SIRT1 elevated the levels of pERK1/2, while inhibition of ERK1/2 counteracted the increase in ?7 nAChR caused by RSV. These findings indicate that neuroprotection by SIRT1 may involve increasing levels of ?7 nAChR through activation of the MAPK/ERK1/2 signaling pathway.

SUBMITTER: Cao K

PROVIDER: S-EPMC7053601 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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The neuroprotective effects of SIRT1 in mice carrying the APP/PS1 double-transgenic mutation and in SH-SY5Y cells over-expressing human APP670/671 may involve elevated levels of α7 nicotinic acetylcholine receptors.

Cao Kun K Dong Yang-Ting YT Xiang Jie J Xu Yi Y Li Yi Y Song Hui H Yu Wen-Feng WF Qi Xiao-Lan XL Guan Zhi-Zhong ZZ

Aging 20200130 2

The aim was to determine whether the neuroprotective effect of SIRT1 in Alzheimer's disease (AD), due to inhibition of aggregation of the β-amyloid peptide (Aβ), involves activation of α7 nAChR. In present study, four-month-old APP/PS1 mice were administered resveratrol (RSV) or suramin once daily for two months, following which their spatial learning and memory were assessed using the Morris water maze test. Deposits of Aβ in vivo were detected by near-infrared imaging (NIRI) and confocal laser ...[more]

PMID: 32003755

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Project description:1. SH-SY5Y cells express alpha7 and alpha3* subtypes of nicotinic acetylcholine receptors (AChR). Numbers of these receptors are upregulated by chronic treatment with nicotinic agonists or KCl. In this study we have examined the functional consequences of these drug treatments on nicotine- or KCl-evoked increases in [Ca(2+)](i), in SH-SY5Y cells. 2. In untreated cells, nicotine increased [Ca(2+)](i) (EC(50) 7.5 microM). Responses to 10 microM nicotine were abolished by the non-selective nicotinic antagonist mecamylamine and were partially blocked by alpha7-selective antagonists, the alpha3beta2*-selective antagonist alpha-conotoxin-MII, and by cadmium and verapamil. 3. After treatment for 4 days with nicotinic agonists, nicotine-evoked increases in [Ca(2+)](i) were significantly decreased by about 25%. Nicotine-evoked responses were paradoxically increased in the presence of acute methyllycaconitine (MLA; an alpha7-selective antagonist) although other alpha7-selective antagonists were without effect, while alpha-conotoxin-MII gave a partial inhibition. The increase observed with MLA was abolished by mecamylamine but not by alpha-conotoxin-MII and was still observed 24 h after chronic nicotine treatment. 4. After treatment for 4 days with KCl, nicotine-evoked increases in [Ca(2+)](i) were also decreased by 25%, but acute MLA was without effect. Responses to 20 mM KCl were unchanged by prior treatment with nicotine or KCl. Treatment for 4 days with 5 microM verapamil reduced responses to both nicotine and KCl by about 50%. 5. Multiple nicotinic AChR subtypes contribute to nicotine-evoked increases in [Ca(2+)](i) in SH-SY5Y cells. Responses to acute nicotine are reduced after chronic nicotine or KCl treatment, with loss of the component attributed to the alpha7 subtype. However, in nicotine-treated cells this effect is reversed when nicotine stimulation is applied in the presence of acute MLA. The antagonist may assist in converting a non-functional alpha7 nicotinic AChR to a conducting state.

Project description:Alzheimer's disease (AD) is a progressive neurodegenerative disorder with an unclear cause. It appears that multiple factors participate in the process of neuronal damage including oxidative stress and accumulation of the protein amyloid ? (A?) in the brain. The search for a treatment for this disorder is essential as current medications are limited to alleviating symptoms and palliative effects. The aim of this study is to investigate the effects of mint extracts on selected mechanisms implicated in the development of AD. To enable a thorough investigation of mechanisms, including effects on ?-secretase (the enzyme that leads to the formation of A?), on A? aggregation, and on oxidative stress and apoptosis pathways, a neuronal cell model, SH-SY5Y cells, was selected. Six Mentha taxa were investigated for their in vitro ?-secretase (BACE) and A?-aggregation inhibition activities. Moreover, their neuroprotective effects on H2O2-induced oxidative stress and apoptosis in SH-SY5Y cells were evaluated through caspase activity. Real-time PCR and Western blot analysis were carried out for the two most promising extracts to determine their effects on signalling pathways in SH-SY5Y cells. All mint extracts had strong BACE inhibition activity. M. requienii extracts showed excellent inhibition of A?-aggregation, while other extracts showed moderate inhibition. M. diemenica and M. requienii extracts lowered caspase activity. Exposure of SH-SY5Y cells to M. diemenica extracts resulted in a decrease in the expression of pro-apoptotic protein, Bax, and an elevation in the anti-apoptotic protein, Bcl-xL, potentially mediated by down-regulation of the ASK1-JNK pathway. These results indicate that mint extracts could prevent the formation of A? and also could prevent their aggregation if they had already formed. M. diemenica and M. requienii extracts have potential to suppress apoptosis at the cellular level. Hence, mint extracts could provide a source of efficacious compounds for a therapeutic approach for AD.

Dataset Information

The neuroprotective effects of SIRT1 in mice carrying the APP/PS1 double-transgenic mutation and in SH-SY5Y cells over-expressing human APP670/671 may involve elevated levels of ?7 nicotinic acetylcholine receptors.

Publications

The neuroprotective effects of SIRT1 in mice carrying the APP/PS1 double-transgenic mutation and in SH-SY5Y cells over-expressing human APP670/671 may involve elevated levels of α7 nicotinic acetylcholine receptors.

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