Adiponectin-mimetic novel nonapeptide rescues aberrant neuronal metabolic-associated memory deficits in Alzheimer's disease.
Adiponectin-mimetic novel nonapeptide rescues aberrant neuronal metabolic-associated memory deficits in Alzheimer's disease.
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DOI：
10.1186/s13024-021-00445-4
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发表时间：
2021-04-13
影响因子：
15.1
通讯作者：
Kim MO
中科院分区：
文献类型：
--
作者：
Ali T;Rehman SU;Khan A;Badshah H;Abid NB;Kim MW;Jo MH;Chung SS;Lee HG;Rutten BPF;Kim MO
最近，我们和其他研究人员报道，大脑代谢紊乱与阿尔茨海默病(AD)有关，AD是一种进行性、破坏性和不可治愈的神经退行性疾病。因此，迫切需要新的治疗方法来探索治疗阿尔茨海默病的潜在和新的治疗靶点/药物。神经型脂联素受体1(AdipoR1)是一个新出现的干预代谢相关AD的潜在靶点。我们的目的是验证这一假说，并深入探讨一种渗透素衍生的脂联素类似物新的九肽(Os-PEP)对代谢相关AD的治疗作用。我们对注射淀粉样蛋白β寡聚体、转基因脂联素基因敲除(ADIPO−/−)和ADIPOR1基因敲除的小鼠的APP/PS1使用了OS-PEP剂量方案(每隔天5 μg/g，连续45 天)。行为学检查结束后，对脑组织进行生化和免疫组织化学分析。在不同的小鼠队列中，进行了电生理定位和高尔基体染色实验。为了验证体内研究，我们使用了高表达人APP瑞典(SWE)/印第安纳(IND)神经母细胞瘤SH-SY5Y细胞，用siRNAs敲除AdipoR1和APMK，按照机制方法用Os-pep等条件处理，并进行进一步的生化分析。我们的体外和体内实验结果表明，Os-PEP具有良好的安全性和神经保护作用，并能穿越血脑屏障。我们发现人类AD脑组织中神经元AdipoR1的水平降低。OS-PEP在AD和ADIPO−/−小鼠中刺激AdipoR1及其下游靶点--AMPK信号通路。机制上，在所有体内和体外研究中，Os-pep通过降低神经元胰岛素抵抗来挽救异常的神经元代谢，并通过调节AdipoR1/AMPK信号来激活下游的胰岛素信号，从而改善AD和ADIPO−/−小鼠的记忆功能，这与改善突触功能和通过AdipoR1依赖的机制而长时程增强有关。我们的发现表明，Os-pep激活AdipoR1/AMPK信号转导，调节神经元胰岛素抵抗和胰岛素信号转导，从而挽救AD和脂联素缺乏模型的记忆缺陷。综上所述，OS-PEP作为一种类似脂联素的新型多肽，有望成为治疗AD和其他神经退行性疾病相关脑代谢异常的潜在候选药物。网上版载有补充材料，可在10.1186/s13024-021-00445-4查阅。
Recently, we and other researchers reported that brain metabolic disorders are implicated in Alzheimer’s disease (AD), a progressive, devastating and incurable neurodegenerative disease. Hence, novel therapeutic approaches are urgently needed to explore potential and novel therapeutic targets/agents for the treatment of AD. The neuronal adiponectin receptor 1 (AdipoR1) is an emerging potential target for intervention in metabolic-associated AD. We aimed to validate this hypothesis and explore in-depth the therapeutic effects of an osmotin-derived adiponectin-mimetic novel nonapeptide (Os-pep) on metabolic-associated AD. We used an Os-pep dosage regimen (5 μg/g, i.p., on alternating days for 45 days) for APP/PS1 in amyloid β oligomer-injected, transgenic adiponectin knockout (Adipo−/−) and AdipoR1 knockdown mice. After behavioral studies, brain tissues were subjected to biochemical and immunohistochemical analyses. In separate cohorts of mice, electrophysiolocal and Golgi staining experiments were performed. To validate the in vivo studies, we used human APP Swedish (swe)/Indiana (ind)-overexpressing neuroblastoma SH-SY5Y cells, which were subjected to knockdown of AdipoR1 and APMK with siRNAs, treated with Os-pep and other conditions as per the mechanistic approach, and we proceeded to perform further biochemical analyses. Our in vitro and in vivo results show that Os-pep has good safety and neuroprotection profiles and crosses the blood-brain barrier. We found reduced levels of neuronal AdipoR1 in human AD brain tissue. Os-pep stimulates AdipoR1 and its downstream target, AMP-activated protein kinase (AMPK) signaling, in AD and Adipo−/− mice. Mechanistically, in all of the in vivo and in vitro studies, Os-pep rescued aberrant neuronal metabolism by reducing neuronal insulin resistance and activated downstream insulin signaling through regulation of AdipoR1/AMPK signaling to consequently improve the memory functions of the AD and Adipo−/− mice, which was associated with improved synaptic function and long-term potentiation via an AdipoR1-dependent mechanism. Our findings show that Os-pep activates AdipoR1/AMPK signaling and regulates neuronal insulin resistance and insulin signaling, which subsequently rescues memory deficits in AD and adiponectin-deficient models. Taken together, the results indicate that Os-pep, as an adiponectin-mimetic novel nonapeptide, is a valuable and promising potential therapeutic candidate to treat aberrant brain metabolism associated with AD and other neurodegenerative diseases. The online version contains supplementary material available at 10.1186/s13024-021-00445-4.
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影响因子：
3.7
作者：
Ito R;Higa M;Goto A;Aoshima M;Ikuta A;Ohashi K;Yokoyama S;Ohno Y;Egawa T;Miyata H;Goto K
通讯作者：
Goto K
DOI：
10.1093/gerona/gly017
发表时间：
2019-02-01
影响因子：
5.1
作者：
Baker, Joshua F.;Newman, Anne B.;Harris, Tamara B.
通讯作者：
Harris, Tamara B.
影响因子：
4.6
作者：
Kim MW;Abid NB;Jo MH;Jo MG;Yoon GH;Kim MO
通讯作者：
Kim MO
DOI：
10.1016/j.bbrc.2006.02.186
发表时间：
2006-05-05
影响因子：
3.1
作者：
Jung, TW;Lee, JY;Cha, BS
通讯作者：
Cha, BS
影响因子：
15.1
作者：
Ramos-Rodriguez JJ;Sanchez-Sotano D;Doblas-Marquez A;Infante-Garcia C;Lubian-Lopez S;Garcia-Alloza M
通讯作者：
Garcia-Alloza M