Laboratory of Neuronal Cytoskeletal protein Regulation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Laboratory of Neuronal Cytoskeletal protein Regulation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA Department of Nephrology, Ningxia People's Hospital, Yinchuan, Ningxia Province, China.
J Alzheimers Dis. 2014;39(4):899-909. doi: 10.3233/JAD-131784.
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.
有多种证据表明，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%。周期蛋白依赖性激酶 5（Cdk5）是一种丝氨酸/苏氨酸蛋白激酶，它与主要存在于神经元和胰腺β细胞中的 p35 或 p39 形成活性复合物。最近的研究表明，Cdk5 活性过度是 AD 中所见神经病理学与糖尿病之间的可能联系。以前，我们鉴定了 P5，一种来自 Cdk5 激活剂 p35 的截短 24-aa 肽，后来修改为 TFP5，以便在 AD 模型小鼠中经腹腔注射后穿透血脑屏障。这种治疗抑制了异常的 Cdk5 活性过度，并显著挽救了这些小鼠的 AD 病理学。本研究探讨了 TFP5 肽在挽救大鼠胚胎皮质神经元高葡萄糖（HG）介导的毒性中的潜力。HG 暴露导致 Cdk5-p25 活性过度和氧化应激，表现为活性氧（ROS）产生增加，谷胱甘肽水平降低和超氧化物歧化酶（SOD）活性降低。它还诱导 tau 的过度磷酸化，神经炎症表现为炎症细胞因子如 TNF-α、IL-1β 和 IL-6 的表达增加以及细胞凋亡。在 HG 暴露前用 TFP5 预处理皮质神经元可抑制 Cdk5-p25 活性过度，并通过降低 ROS 水平显著减轻氧化应激，同时增加 SOD 活性和谷胱甘肽水平。用 TFP5 预处理还可显著减少 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 型糖尿病治疗的一种新型候选药物。
