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.

中文翻译：

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脂联素模拟物新型九肽可挽救阿尔茨海默病中异常的神经元代谢相关记忆缺陷

最近，我们和其他研究人员报告说，大脑代谢紊乱与阿尔茨海默病 (AD) 有关联，这是一种进行性、破坏性和无法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 AD 的潜在和新的治疗靶点/药物。神经元脂联素受体 1 (AdipoR1) 是干预代谢相关 AD 的新兴潜在目标。我们旨在验证这一假设并深入探索渗透蛋白衍生的脂联素模拟新型九肽 (Os-pep) 对代谢相关 AD 的治疗作用。我们在注射淀粉样蛋白 β 寡聚体的转基因脂联素敲除 (Adipo-/-) 和 AdipoR1 敲除小鼠中对 APP/PS1 使用 Os-pep 剂量方案（5 μg/g，ip，连续 45 天）。在行为研究之后，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，进行了电生理和高尔基体染色实验。为了验证体内研究，我们使用了人类 APP 瑞典 (swe)/印第安纳 (ind) 过度表达的神经母细胞瘤 SH-SY5Y 细胞，这些细胞用 siRNA 敲低了 AdipoR1 和 APMK，并按照 Os-pep 和其他条件进行了处理。机械方法，我们继续进行进一步的生化分析。我们的体外和体内结果表明，Os-pep 具有良好的安全性和神经保护特性，并且可以穿过血脑屏障。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 及其下游靶标 AMP 活化蛋白激酶 (AMPK) 信号传导。从机制上讲，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 信号激活下游胰岛素信号，从而改善 AD 和 Adipo-/- 小鼠的记忆功能，这与通过 AdipoR1 依赖机制改善的突触功能和长期增强有关。我们的研究结果表明，Os-pep 激活 AdipoR1/AMPK 信号传导并调节神经元胰岛素抵抗和胰岛素信号传导，随后在 AD 和脂联素缺乏模型中挽救记忆缺陷。综上所述，结果表明 Os-pep 作为一种脂联素模拟物的新型九肽，