在一項(xiàng)新的研究中,，來自美國國家衛(wèi)生研究院的研究人員證實(shí)當(dāng)把一種被稱作TFP5的分子注射到患有阿爾茨海默病(Alzheimer's disease,， AD)的模式小鼠體內(nèi)時(shí)，它們的癥狀被逆轉(zhuǎn),，它們的記憶也得到恢復(fù),，同時(shí)沒有明顯的毒副作用.相關(guān)研究結(jié)果發(fā)表在2013年1月那期FASEB Journal期刊上。
論文通信作者Harish C. Pant博士說,，“根據(jù)對小鼠開展的TFP5治療,，我們希望在AD病人體內(nèi)開展的臨床試驗(yàn)應(yīng)當(dāng)能夠延長他們的壽命和改善他們的生活質(zhì)量.因此，我們認(rèn)為TFP5應(yīng)當(dāng)是一種有效的治療性化合物.”
為了作出這一發(fā)現(xiàn),，Pant和同事們利用患有AD的模式小鼠開展研究.一組小鼠被注射這種小分子TFP5,，而另一組被注射生理鹽水作為安慰劑.在進(jìn)行一系列腹腔內(nèi)注射TFP5之后，這組接受治療的小鼠在多種疾病癥狀上表現(xiàn)出顯著性下降,，同時(shí)在視力上也得到恢復(fù).此外,，接受TFP5注射的小鼠并沒有產(chǎn)生體重下降、神經(jīng)焦慮或毒性癥狀.然而接受安慰劑注射的小鼠與期待中的那樣發(fā)生病情惡化.TFP5是源自大腦中的一種關(guān)鍵性的被稱作Cdk5的酶的調(diào)節(jié)分子.Cdk5過度激活參與斑塊和神經(jīng)元纖維纏結(jié)產(chǎn)生，其中斑塊和神經(jīng)元纖維纏結(jié)是AD的主要特征.
FASEB Journal期刊主編Gerald Weissmann博士說,，“下一步就是證實(shí)這種分子在人們體內(nèi)是否能夠擁有相同的效果,，如果沒有的話，那么就去尋找哪些分子將擁有.鑒于我們知道我們能夠靶向阿爾茨海默病中的基礎(chǔ)性分子缺陷,，因此我們希望能夠找到比現(xiàn)在的治療方法更好的和更加特異性的療法.”(生物谷Bioon.com)
doi: 10.1096/fj.12-217497
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A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model mice
Varsha Shukla*, Ya-Li Zheng§, Santosh K. Mishra‡, Niranjana D. Amin*, Joseph Steiner†, Philip Grant*, Sashi Kesavapany‖ and Harish C. Pant*,1
Alzheimer's disease (AD), one of the leading neurodegenerative disorders of older adults, which causes major socioeconomic burdens globally, lacks effective therapeutics without significant side effects. Besides the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs), it has been reported that cyclin-dependent kinase 5 (Cdk5), a critical neuronal kinase, is hyperactivated in AD brains and is, in part, responsible for the above pathology. Here we show that a modified truncated 24-aa peptide (TFP5), derived from the Cdk5 activator p35, penetrates the blood-brain barrier after intraperitoneal injections, inhibits abnormal Cdk5 hyperactivity, and significantly rescues AD pathology (up to 70–80%) in 5XFAD AD model mice. The mutant mice, injected with TFP5 exhibit behavioral rescue, whereas no rescue was observed in mutant mice injected with either saline or scrambled peptide. However, TFP5 does not inhibit cell cycle Cdks or normal Cdk5/p35 activity, and thereby has no toxic side effects (even at 200 mg/kg), a common problem in most current therapeutics for AD. In addition, treated mice displayed decreased inflammation, amyloid plaques, NFTs, cell death, and an extended life by 2 mo. These results suggest TFP5 as a potential therapeutic, toxicity-free candidate for AD.—Shukla, V., Zheng, Y.-L., Mishra, S. K., Amin, N. D., Steiner, J., Grant, P., Kesavapany, S., Pant, H. C. A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model mice.
