Chronic oral administration of adipoRon reverses cognitive impairments and ameliorates neuropathology in an Alzheimer's disease mouse model
Chronic oral administration of adipoRon reverses cognitive impairments and ameliorates neuropathology in an Alzheimer's disease mouse model
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DOI：
10.1038/s41380-020-0701-0
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发表时间：
2020-03-04
影响因子：
11
通讯作者：
Chan, Koon-Ho
中科院分区：
文献类型：
--
作者：
Ng, Roy Chun-Laam;Jian, Min;Chan, Koon-Ho
循环脂联素（APN）水平随着年龄和肥胖而降低。另一方面，APN水平的降低与神经变性和神经炎症相关。我们以前发现，老年脂联素基因敲除（APN（-/-））小鼠发展阿尔茨海默病样病变，脑胰岛素抵抗，认知障碍。最近，我们还证明了APN缺乏增加了5xFAD小鼠中A β诱导的小胶质细胞活化和神经炎症反应。有令人信服的证据表明，失调的胰岛素活性或脑胰岛素抵抗有助于神经炎症和阿尔茨海默病（AD）的发病机制。在这里，我们证明了APN水平在AD患者和5xFAD小鼠的大脑中降低。我们将5xFAD小鼠与APN（-/-）小鼠杂交以产生APN缺陷型5xFAD（5xFAD;APN（-/-））。5xFAD小鼠中APN缺乏加速淀粉样蛋白负荷，增加脑淀粉样血管病，并降低胰岛素信号传导活性。药代动力学研究表明，脂联素（APN受体激动剂）是一种血脑屏障渗透剂。AdipoRon在体外和体内改善神经元胰岛素信号传导活性和胰岛素敏感性。在5xFAD和5xFAD;APN（-/-）小鼠中，长期adipoRon治疗改善了空间记忆功能，并显著挽救了神经元和突触损失。AdipoRon降低了AD小鼠的斑块和A β水平。AdipoRon还通过减少小胶质细胞和星形胶质细胞的活化以及抑制脑细胞因子水平来发挥抗炎作用。adipoRon处理后，小胶质细胞对A β的吞噬活性恢复。我们的研究结果表明，adipoRon发挥多种有益作用，提供重要的治疗意义。我们建议长期adipoRon给药作为AD的潜在治疗方法。
Circulating adiponectin (APN) levels decrease with age and obesity. On the other hand, a reduction in APN levels is associated with neurodegeneration and neuroinflammation. We previously showed that aged adiponectin knockout (APN(-/-)) mice developed Alzheimer's like pathologies, cerebral insulin resistance, and cognitive impairments. More recently, we also demonstrated that APN deficiency increased A beta-induced microglia activation and neuroinflammatory responses in 5xFAD mice. There is compelling evidence that deregulated insulin activities or cerebral insulin resistance contributes to neuroinflammation and Alzheimer's disease (AD) pathogenesis. Here, we demonstrated that APN levels were reduced in the brain of AD patients and 5xFAD mice. We crossbred 5xFAD mice with APN(-/-) mice to generate APN-deficient 5xFAD (5xFAD;APN(-/-)). APN deficiency in 5xFAD mice accelerated amyloid loading, increased cerebral amyloid angiopathy, and reduced insulin-signaling activities. Pharmacokinetics study demonstrated adipoRon (APN receptor agonist) was a blood-brain barrier penetrant. AdipoRon improved neuronal insulin-signaling activities and insulin sensitivity in vitro and in vivo. Chronic adipoRon treatment improved spatial memory functions and significantly rescued neuronal and synaptic loss in 5xFAD and 5xFAD;APN(-/-) mice. AdipoRon lowered plaque and A beta levels in AD mice. AdipoRon also exerted anti-inflammatory effects by reducing microglial and astrocytes activation as well as suppressing cerebral cytokines levels. The microglial phagocytic activity toward A beta was restored after adipoRon treatment. Our results indicated that adipoRon exerts multiple beneficial effects providing important therapeutic implications. We propose chronic adipoRon administration as a potential treatment for AD.