TFP5, a peptide derived from p35, a Cdk5 neuronal activator, rescues cortical neurons from glucose toxicity.
TFP5, a peptide derived from p35, a Cdk5 neuronal activator, rescues cortical neurons from glucose toxicity.
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DOI：
10.3233/jad-131784
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Pant HC
中科院分区：
文献类型：
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作者：
Binukumar BK;Zheng YL;Shukla V;Amin ND;Grant P;Pant HC
多种证据表明糖尿病的发病率与阿尔茨海默病 (AD) 的发展有关。糖尿病患者患 AD 的风险增加 50% 至 75%。细胞周期蛋白依赖性激酶 5 (Cdk5) 是一种丝氨酸/苏氨酸蛋白激酶，它与 p35 或 p39 形成活性复合物，主要存在于神经元和胰腺 β 细胞中。最近的研究表明，Cdk5 过度活跃可能是 AD 中神经病理学与糖尿病之间的联系。此前，我们鉴定了P5，一种源自Cdk5激活剂p35的截短的24个氨基酸的肽，后来被修饰为TFP5，以便在AD模型小鼠腹腔注射后能够穿透血脑屏障。这种治疗抑制了异常的 Cdk5 过度活跃，并显着挽救了这些小鼠的 AD 病理。本研究探讨了 TFP5 肽拯救大鼠胚胎皮质神经元高葡萄糖 (HG) 介导的毒性的潜力。 HG 暴露会导致 Cdk5-p25 过度活跃和氧化应激，其特征是活性氧产生增加、谷胱甘肽水平和超氧化物歧化酶活性降低。它还会诱导 tau 蛋白过度磷酸化、神经炎症（从 TNF-α、IL-1β 和 IL-6 等炎症细胞因子的表达增加可以看出）以及细胞凋亡。在 HG 暴露之前用 TFP5 预处理皮质神经元可抑制 Cdk5-p25 过度活跃，并通过降低活性氧水平、同时增加超氧化物歧化酶活性和谷胱甘肽来显着减轻氧化应激。 TFP5 预处理也显着减少了 HG 诱导的 Tau 过度磷酸化、炎症和细胞凋亡。这些结果表明 TFP5 肽可能是 2 型糖尿病治疗的新候选者。
Multiple lines of evidence link the incidence of diabetes to the development of Alzheimer’s disease (AD). Patients with diabetes have a 50 to 75% increased risk of developing AD. Cyclin dependent kinase 5 (Cdk5) is a serine/threonine protein kinase, which forms active complexes with p35 or p39, found principally in neurons and in pancreatic β cells. Recent studies suggest that Cdk5 hyperactivity is a possible link between neuropathology seen in AD and diabetes. Previously, we identified P5, a truncated 24-aa peptide derived from the Cdk5 activator p35, later modified as TFP5, so as to penetrate the blood-brain barrier after intraperitoneal injections in AD model mice. This treatment inhibited abnormal Cdk5 hyperactivity and significantly rescued AD pathology in these mice. The present study explores the potential of TFP5 peptide to rescue high glucose (HG)-mediated toxicity in rat embryonic cortical neurons. HG exposure leads to Cdk5- p25 hyperactivity and oxidative stress marked by increased reactive oxygen species production, and decreased glutathione levels and superoxide dismutase activity. It also induces hyperphosphorylation of tau, neuroinflammation as evident from the increased expression of inflammatory cytokines like TNF-α, IL-1β, and IL-6, and apoptosis. Pretreatment of cortical neurons with TFP5 before HG exposure inhibited Cdk5-p25 hyperactivity and significantly attenuated oxidative stress by decreasing reactive oxygen species levels, while increasing superoxide dismutase activity and glutathione. Tau hyperphosphorylation, inflammation, and apoptosis induced by HG were also considerably reduced by pretreatment with TFP5. These results suggest that TFP5 peptide may be a novel candidate for type 2 diabetes therapy.