The Second Department of Geriatrics, Ninth Hospital of Xi'an, Xi'an, China.
Department of Endocrinology, Ninth Hospital of Xi'an, Xi'an, China.
Neurobiol Learn Mem. 2020 Mar;169:107155. doi: 10.1016/j.nlm.2019.107155. Epub 2020 Jan 2.
Diabetic rats display cognition impairments accompanied by activation of NF-κB signalling and increased Aβ expression. Ghrelin has been suggested to improve cognition in diabetic rats. In this study, we investigated the role of ghrelin on cognition and NF-κB mediated Aβ production in diabetic rats. A diabetic rat model was established with streptozotocin (STZ) injection, and diabetic rats were intracerebroventricularly administered with ghrelin or (D-lys3)-GHRP-6 (DG). Our results showed that diabetic rats had cognition impairment in the Morris water maze test, accompanied by the higher expression of Aβ in the hippocampus. Western blot analysis showed that diabetic rats exhibited significantly decreased levels of GHSR-1a and protein phosphatase 1 (PP1) in the hippocampus and increased activation of the IKK/NF-κB/BACE1 pathway. Chronic ghrelin administration upregulated hippocampal PP1 expression, suppressed IKK/NF-κB/BACE1 mediated Aβ production, and improved cognition in STZ-induced diabetic rats. These effects were reversed by DG. Then, primary rat hippocampal neurons were isolated and treated with high glucose, followed by Ghrelin and DG, PP1 or IKK. Similar to the in vivo results, high glucose suppressed the expression levels of GHSR-1a and PP1, activated the IKK/NF-κB/BACE1 pathway, increased Aβ production. Ghrelin suppressed IKK/NF-κB/BACE1 induced Aβ production. This improvement was reversed by DG and a PP1 antagonist and was enhanced by the IKK antagonist. Our findings indicated that chronic ghrelin administration can suppress IKK/NF-κB/BACE1 mediated Aβ production in primary neurons with high glucose treatment and improve the cognition via PP1 upregulation in diabetic rats.
糖尿病大鼠表现出认知障碍，伴随着 NF-κB 信号的激活和 Aβ 表达的增加。胃饥饿素被认为可以改善糖尿病大鼠的认知能力。在这项研究中，我们研究了胃饥饿素对糖尿病大鼠认知和 NF-κB 介导的 Aβ 产生的作用。通过链脲佐菌素（STZ）注射建立糖尿病大鼠模型，并通过脑室内给予胃饥饿素或（D-lys3）-GHRP-6（DG）治疗糖尿病大鼠。我们的结果表明，糖尿病大鼠在 Morris 水迷宫测试中表现出认知障碍，同时海马区 Aβ 的表达增加。Western blot 分析显示，糖尿病大鼠海马区 GHSR-1a 和蛋白磷酸酶 1（PP1）水平显著降低，IKK/NF-κB/BACE1 通路激活增加。慢性胃饥饿素给药上调海马区 PP1 表达，抑制 IKK/NF-κB/BACE1 介导的 Aβ 产生，改善 STZ 诱导的糖尿病大鼠认知功能。这些作用被 DG 逆转。然后，分离原代大鼠海马神经元，用高葡萄糖处理，再用 Ghrelin 和 DG、PP1 或 IKK 处理。与体内结果相似，高葡萄糖抑制 GHSR-1a 和 PP1 的表达水平，激活 IKK/NF-κB/BACE1 通路，增加 Aβ 的产生。Ghrelin 抑制 IKK/NF-κB/BACE1 诱导的 Aβ 产生。这种改善被 DG 和 PP1 拮抗剂逆转，并被 IKK 拮抗剂增强。我们的研究结果表明，慢性胃饥饿素给药可以通过上调 PP1 抑制高葡萄糖处理的原代神经元中 IKK/NF-κB/BACE1 介导的 Aβ 产生，并改善糖尿病大鼠的认知功能。
