Shukla Varsha, Seo Jinsoo, Binukumar B K, Amin Niranjana D, Reddy Preethi, Grant Philip, Kuntz Susan, Kesavapany Sashi, Steiner Joseph, Mishra Santosh K, Tsai Li-Huei, Pant Harish C
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Department of Brain and Cognitive Sciences, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
J Alzheimers Dis. 2017;56(1):335-349. doi: 10.3233/JAD-160916.
It has been reported that cyclin-dependent kinase 5 (cdk5), a critical neuronal kinase, is hyperactivated in Alzheimer's disease (AD) and may be, in part, responsible for the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs). It has been proposed by several laboratories that hyperactive cdk5 results from the overexpression of p25 (a truncated fragment of p35, the normal cdk5 regulator), which, when complexed to cdk5, induces hyperactivity, hyperphosphorylated tau/NFTs, amyloid-β plaques, and neuronal death. It has previously been shown that intraperitoneal (i.p.) injections of a modified truncated 24-aa peptide (TFP5), derived from the cdk5 activator p35, penetrated the blood-brain barrier and significantly rescued AD-like pathology in 5XFAD model mice. The principal pathology in the 5XFAD mutant, however, is extensive amyloid plaques; hence, as a proof of concept, we believe it is essential to demonstrate the peptide's efficacy in a mouse model expressing high levels of p25, such as the inducible CK-p25Tg model mouse that overexpresses p25 in CamKII positive neurons. Using a modified TFP5 treatment, here we show that peptide i.p. injections in these mice decrease cdk5 hyperactivity, tau, neurofilament-M/H hyperphosphorylation, and restore synaptic function and behavior (i.e., spatial working memory, motor deficit using Rota-rod). It is noteworthy that TFP5 does not inhibit endogenous cdk5/p35 activity, nor other cdks in vivo suggesting it might have no toxic side effects, and may serve as an excellent therapeutic candidate for neurodegenerative disorders expressing abnormally high brain levels of p25 and hyperactive cdk5.
据报道，细胞周期蛋白依赖性激酶5（cdk5）是一种关键的神经元激酶，在阿尔茨海默病（AD）中过度激活，可能部分导致淀粉样斑块和神经原纤维缠结（NFTs）这一标志性病理特征。几个实验室提出，cdk5过度激活是由于p25（正常cdk5调节因子p35的截短片段）过度表达所致，当p25与cdk5结合时，会诱导激酶活性增强、tau蛋白过度磷酸化/NFTs形成、淀粉样β斑块形成以及神经元死亡。此前已表明，腹腔注射源自cdk5激活剂p35的修饰截短24氨基酸肽（TFP5）可穿透血脑屏障，并显著挽救5XFAD模型小鼠的AD样病理特征。然而，5XFAD突变体的主要病理特征是广泛的淀粉样斑块；因此，作为概念验证，我们认为有必要在表达高水平p25的小鼠模型中证明该肽的疗效，例如在CaMKII阳性神经元中过度表达p25的诱导型CK-p25Tg模型小鼠。通过使用改良的TFP5治疗，我们在此表明，对这些小鼠进行肽腹腔注射可降低cdk5过度激活、tau蛋白、神经丝-M/H过度磷酸化，并恢复突触功能和行为（即空间工作记忆、使用转棒试验检测的运动缺陷）。值得注意的是，TFP5在体内并不抑制内源性cdk5/p35活性，也不抑制其他细胞周期蛋白依赖性激酶，这表明它可能没有毒副作用，并且可能是治疗p25脑内水平异常高且cdk5过度激活的神经退行性疾病的优秀候选药物。
