阿爾茨海默癥（AD)是一種逐漸惡化的神經(jīng)退行性疾病，目前為止,，全球大約有2400萬患者,。傳統(tǒng)理論認(rèn)為，在AD患者中淀粉樣蛋白在大腦中積聚,，形成色斑狀物質(zhì),，造成對(duì)大腦功能的損害。美國(guó)加利福尼亞州巴克老年研究所提出了阿爾茨海默癥的一個(gè)新演化模型,。新研究發(fā)現(xiàn)認(rèn)為AD可能是神經(jīng)元傳遞信號(hào)失控所致,。該研究發(fā)表在1 月刊出的Cell Death and Differentiation雜志上。
這項(xiàng)研究得到法國(guó)國(guó)家科研中心,、美國(guó)國(guó)立衛(wèi)生研究院,、Joseph Drown基金會(huì)、John Douglas French基金會(huì)和AD協(xié)會(huì)的資助,。
AD的謎團(tuán)之一是關(guān)于聚集在神經(jīng)元聯(lián)接部位的淀粉樣前體蛋白（APP）的功能。盡管此前普遍認(rèn)為作為AD標(biāo)志的色斑狀物質(zhì)來自于APP,，但有理由認(rèn)為APP的存在本身并不會(huì)導(dǎo)致AD,。在最新的研究中發(fā)現(xiàn)，APP結(jié)合到蛋白Netrin-1上，后者除輔助神經(jīng)細(xì)胞存活外,，也參與大腦神經(jīng)和神經(jīng)聯(lián)接功能,。一旦給予具有AD 癥狀的小鼠Netrin-1 蛋白，小鼠癥狀逆轉(zhuǎn),，色斑狀物質(zhì)開始消減,。
這些研究提示，長(zhǎng)期以來所認(rèn)為的淀粉樣色斑導(dǎo)致神經(jīng)細(xì)胞壞死促使AD 發(fā)生的理念可能是錯(cuò)誤的,；相反,，在Netrin-1 促進(jìn)神經(jīng)元聯(lián)接形成與淀粉樣色斑破壞神經(jīng)元聯(lián)接共同作用下，AD可能源于大腦中正常神經(jīng)聯(lián)接建立和破壞的動(dòng)態(tài)平衡的失控,。需要指出的是,，結(jié)合到APP上的Netrin-1不僅維持神經(jīng)細(xì)胞的存活和聯(lián)接，同時(shí)也關(guān)閉淀粉樣物質(zhì)的合成,，從而使得Netrin-1 成為一種極具潛力的治療藥物,。
APP 是正常記憶和失憶功能中的可塑性模塊分子，而Netrin-1是恢復(fù)正常平衡狀態(tài)的重點(diǎn),。研究人員表示,，將研究因失控導(dǎo)致AD信號(hào)通路發(fā)生的變化。根據(jù)這項(xiàng)研究,，一種新藥研發(fā)工作正在進(jìn)行中,。巴克老年研究所和法國(guó)國(guó)家科研中心（CNRS）當(dāng)前正與神經(jīng)生物技術(shù)公司（Neurobiological Technologies,Inc.）展開合作，力圖將這項(xiàng)研究成果產(chǎn)業(yè)化,。（生物谷Bioon.com）
生物谷推薦原始出處：
Cell Death and Differentiation (2009) 16, 655–663; doi:10.1038/cdd.2008.191
Netrin-1 interacts with amyloid precursor protein and regulates amyloid-β production
Edited by M Deshmukh
F C Louren?o1, V Galvan2,4, J Fombonne1,4, V Corset1,4, F Llambi1, U Müller3, D E Bredesen2,5 and P Mehlen1,2,5
1Apoptosis, Cancer and Development Laboratory – Equipe labellisée ‘La Ligue’, CNRS UMR5238, Centre Léon Bérard, University of Lyon., 69008 Lyon, France
2The Buck Institute for Age Research, Novato, CA 94945, USA
3Institute for Pharmacy and Molecular Biotechnology (IPMB), University of Heidelberg, Germany
The β-amyloid precursor protein (APP) is an orphan transmembrane receptor whose physiological role is largely unknown. APP is cleaved by proteases generating amyloid-β (Aβ) peptide, the main component of the amyloid plaques that are associated with Alzheimer's disease. Here, we show that APP binds netrin-1, a multifunctional guidance and trophic factor. Netrin-1 binding modulates APP signaling triggering APP intracellular domain (AICD)-dependent gene transcription. Furthermore, netrin-1 binding suppresses Aβ peptide production in brain slices from Alzheimer model transgenic mice. In this mouse model, decreased netrin-1 expression is associated with increased Aβ concentration, thus supporting netrin-1 as a key regulator of Aβ production. Finally, we show that netrin-1 brain administration in Alzheimer model transgenic mice may be associated with an amelioration of the Alzheimer's phenotype.
