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 Aβ-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 Aβ 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 Aβ 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.

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有关。我们之前表明，年老的脂联素敲除 ( APN ^-/- ) 小鼠会出现阿尔茨海默病样病变、脑胰岛素抵抗和认知障碍。最近，我们还证明 APN 缺乏会增加 5xFAD 小鼠中 Aβ 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 AD 患者和 5xFAD 小鼠大脑中的 APN 水平降低。我们将 5xFAD 小鼠与APN杂交^-/-小鼠产生 APN 缺陷的 5xFAD (5xFAD; APN ^-/- )。5xFAD 小鼠的 APN 缺乏加速了淀粉样蛋白负荷，增加了脑淀粉样蛋白血管病，并降低了胰岛素信号传导活动。药代动力学研究表明，adipoRon（APN 受体激动剂）是一种血脑屏障渗透剂。AdipoRon 在体外和体内改善了神经元胰岛素信号传导活性和胰岛素敏感性。慢性adipoRon 治疗改善了空间记忆功能，并显着挽救了 5xFAD 和 5xFAD 中的神经元和突触损失；APN ^-/-老鼠。AdipoRon 降低了 AD 小鼠的斑块和 Aβ 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发挥抗炎作用。在adipoRon处理后，小胶质细胞对Aβ的吞噬活性得到恢复。我们的结果表明，adipoRon 发挥多种有益作用，提供重要的治疗意义。我们建议长期使用adipoRon 作为AD 的潜在治疗方法。