[P3–136]: NEC‐1 ALLEVIATES COGNITIVE IMPAIRMENT WITH REDUCTION OF Aβ AND TAU ABNORMALITIES IN APP/PS1 MICE

Yang, Seung‐Hoon; Lee, Dongkeun; Shin, Jisu; Lee, Se-Jin; Baek, Seungyeop; Kim, Youngsoo

doi:10.1016/j.jalz.2017.06.1347

Cited by 21 publications

(33 citation statements)

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“…β‐Amyloid (Aβ) plaques and neurofibrillary tangles are key neuropathological hallmarks in AD (Perez et al, ). Accumulation of Aβ peptide leads to synaptic loss (Zempel et al, ), neuronal death (He et al, ), and memory deficits (Yang et al, ), and the decrease in hippocampal synaptic plasticity is an early event in the pathogenesis of AD (Styr & Slutsky, ). Recently, some epidemiological researches have reported the negative association between AD and cancer, which means older persons with AD dementia have a reduced risk of cancer and vice versa (Calderwood & Murshid, ; Nixon, ; Shafi, ).…”

Section: Introductionmentioning

confidence: 99%

Increased miR‐34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS‐JNK‐p53 pathway in Alzheimer’s Disease

Shi

Zhang

Zhou³

et al. 2020

Aging Cell

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Alzheimer's disease (AD) and cancer have inverse relationship in many aspects. Some tumor suppressors, including miR‐34c, are decreased in cancer but increased in AD. The upstream regulatory pathways and the downstream mechanisms of miR‐34c in AD remain to be investigated. The expression of miR‐34c was detected by RT–qPCR in oxidative stressed neurons, hippocampus of SAMP8 mice, or serum of patients with amnestic mild cognitive impairment (aMCI). Dual luciferase assay was performed to confirm the binding sites of miR‐34c in its target mRNA. The Morris water maze (MWM) was used to evaluate learning and memory in SAMP8 mice administrated with miR‐34c antagomir (AM34c). Golgi staining was used to evaluate the synaptic function and structure. The dramatically increased miR‐34c was mediated by ROS‐JNK‐p53 pathway and negatively regulated synaptotagmin 1 (SYT1) expression by targeting the 3′‐untranslated region (3′‐UTR) of syt1 in AD. The expression of SYT1 protein was reduced by over expression of miR‐34c in the HT‐22 cells and vice versa. Administration of AM34c by the third ventricle injection or intranasal delivery markedly increased the brain levels of SYT1 and ameliorated the cognitive function in SAMP8 mice. The serum miR‐34c was significantly increased in patients with aMCI and might be a predictive biomarker for diagnosis of aMCI. These results indicated that increased miR‐34c mediated synaptic and memory deficits by targeting SYT1 through ROS‐JNK‐p53 pathway and the miR‐34c/SYT1 pathway could be considered as a promising novel therapeutic target for patients with AD.

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Section: Introductionmentioning

confidence: 99%

Increased miR‐34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS‐JNK‐p53 pathway in Alzheimer’s Disease

Shi

Zhang

Zhou³

et al. 2020

Aging Cell

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“…The cells were pre-treated with various concentrations of Nec-1 (1-40 μM) for 30 min followed by 24 h exposure to cell damaging factors (H 2 O 2 , 6-OHDA, Glu). The chosen concentrations of Nec-1 were based on literature search and included not active (< 1 μM) and RIP1-specific (> 3 μM) concentrations (Degterev et al 2008;Ito et al 2017;Yamanaka et al 2011;Yang et al 2017bYang et al , 2019. For comparison of the Nec-1 effects with other protectants, the antioxidant, Nacetylcysteine (NAC, 1 mM), and curcumin (Curc, 5 μM) were used.…”

Section: Cell Treatmentmentioning

confidence: 99%

Neuroprotective Effects of Necrostatin-1 Against Oxidative Stress–Induced Cell Damage: an Involvement of Cathepsin D Inhibition

et al. 2020

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Necroptosis, a recently discovered form of non-apoptotic programmed cell death, can be implicated in many pathological conditions including neuronal cell death. Moreover, an inhibition of this process by necrostatin-1 (Nec-1) has been shown to be neuroprotective in in vitro and in vivo models of cerebral ischemia. However, the involvement of this type of cell death in oxidative stress-induced neuronal cell damage is less recognized. Therefore, we tested the effects of Nec-1, an inhibitor of necroptosis, in the model of hydrogen peroxide (H 2 O 2)-induced cell damage in human neuroblastoma SH-SY5Y and murine hippocampal HT-22 cell lines. The data showed that Nec-1 (10-40 μM) attenuated the cell death induced by H 2 O 2 in undifferentiated (UN-) and neuronal differentiated (RA-) SH-SY5Y cells with a higher efficacy in the former cell type. Moreover, Nec-1 partially reduced cell damage induced by 6-hydroxydopamine in UN-and RASH -SY5Y cells. The protective effect of Nec-1 was of similar magnitude as the effect of a caspase-3 inhibitor in both cell phenotypes and this effect were not potentiated after combined treatment. Furthermore, the non-specific apoptosis and necroptosis inhibitor curcumin augmented the beneficial effect of Nec-1 against H 2 O 2-evoked cell damage albeit only in RASH -SY5Y cells. Next, it was found that the mechanisms of neuroprotective effect of Nec-1 against H 2 O 2induced cell damage in SH-SY5Y cells involved the inhibition of lysosomal protease, cathepsin D, but not caspase-3 or calpain activities. In HT-22 cells, Nec-1 was protective in two models of oxidative stress (H 2 O 2 and glutamate) and that effect was blocked by a caspase inhibitor. Our data showed neuroprotective effects of the necroptosis inhibitor, Nec-1, against oxidative stress-induced cell damage and pointed to involvement of cathepsin D inhibition in the mechanism of its action. Moreover, a cell type-specific interplay between necroptosis and apoptosis has been demonstrated.

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“…5 The mRNA expression after SH-SY5Y cells transfected with si-RIP1. ( **** p < 0.0001) exposed cells to TNPs with or without Nec-1 (a potent necroptosis inhibitor) [17,18], and measured the cell viability, LDH leakage, and the levels of inflammatory cytokines. Our data suggest that Nec-1 co-treatment can mitigate inflammatory injury induced by TNPs.…”

Section: Discussionmentioning

confidence: 99%

Nec-1 Attenuates Neurotoxicity Induced by Titanium Dioxide Nanomaterials on Sh-Sy5y Cells Through RIP1

Zhou

Huang

et al. 2020

Nanoscale Res Lett

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Titanium dioxide nanomaterials are applied in numerous fields due to their splendid physicochemical characteristics, which in turn poses a potential threat to human health. Recently, numerous in vivo studies have revealed that titanium dioxide nanoparticles (TNPs) can be transported into animal brains after exposure through various routes. Absorbed TNPs can accumulate in the brain and may disturb neuronal cells, leading to brain dysfunction. In vitro studies verified the neurotoxicity of TNPs. The mechanisms underlying the neurotoxicity of TNPs remains unclear. Whether necroptosis is involved in the neurotoxicity of TNPs is unknown. Therefore, we performed an in vitro study and found that TNPs induced inflammatory injury in SH-SY5Y cells in a dose-dependent way, which was mitigated by necrostatin-1 (Nec-1) pretreatment. Since receptor-interacting protein kinase 1 (RIP1) is reported to be the target of Nec-1, we silenced it by siRNA. We exposed mutant and wild-type cells to TNPs and assessed inflammatory injury. Silencing RIP1 expression inhibited inflammatory injury induced by TNPs exposure. Taken together, Nec-1 ameliorates the neurotoxicity of TNPs through RIP1. However, more studies should be performed to comprehensively assess the correlation between the neurotoxicity of TNPs and RIP1.

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[P3–136]: NEC‐1 ALLEVIATES COGNITIVE IMPAIRMENT WITH REDUCTION OF Aβ AND TAU ABNORMALITIES IN APP/PS1 MICE

Cited by 21 publications

References 0 publications

Increased miR‐34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS‐JNK‐p53 pathway in Alzheimer’s Disease

Increased miR‐34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS‐JNK‐p53 pathway in Alzheimer’s Disease

Neuroprotective Effects of Necrostatin-1 Against Oxidative Stress–Induced Cell Damage: an Involvement of Cathepsin D Inhibition

Nec-1 Attenuates Neurotoxicity Induced by Titanium Dioxide Nanomaterials on Sh-Sy5y Cells Through RIP1

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