人們主要以從對腦組織尸檢獲得的證據(jù)為依據(jù)認為，tau蛋白的異常纖維性沉積（該蛋白在正常發(fā)揮功能時其作用是穩(wěn)定微管）在阿爾茨海默氏癥和tau-相關(guān)額顳癡呆癥中引起細胞凋亡和神經(jīng)退化,。
現(xiàn)在,，對過度表達一種人類tau基因的轉(zhuǎn)基因小鼠中的這些神經(jīng)纖維糾結(jié)所做的活體多光子成像研究，顯示了一個大相徑庭的情形,。半胱天冬酶激發(fā)（細胞凋亡的一個已知標志）是所觀察到的第一個異常,，發(fā)生在糾結(jié)形成之前數(shù)小時至數(shù)天。有糾結(jié)的神經(jīng)細胞不是遭受死亡,，而是好像壽命還很長,，同時半胱天冬酶活性降低。因此真實情況可能是這樣的：引起神經(jīng)退化的是可溶性tau,，而不是纖維性tau,。
就以破壞糾結(jié)為目標的藥物在對抗神經(jīng)退化中的價值上而言，這項工作的意思在很大程度上取決于神經(jīng)纖維糾結(jié)是一種與疾病無關(guān)的保護性因子還是與慢性神經(jīng)毒性相關(guān),。(生物谷Bioon.com)
生物谷推薦原文出處：
Nature doi:10.1038/nature08890
Caspase activation precedes and leads to tangles
Alix de Calignon1,2, Leora M. Fox1, Rose Pitstick3, George A. Carlson3, Brian J. Bacskai1, Tara L. Spires-Jones1 & Bradley T. Hyman1
MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Alzheimer’s Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
Université Pierre and Marie Curie, Paris 75005, France
McLaughlin Research Institute, Great Falls, Montana 59401, USA
Studies of post-mortem tissue have shown that the location of fibrillar tau deposits, called neurofibrillary tangles (NFT), matches closely with regions of massive neuronal death1, 2, severe cytological abnormalities3, and markers of caspase activation and apoptosis4, 5, 6, leading to the idea that tangles cause neurodegeneration in Alzheimer’s disease and tau-related frontotemporal dementia. However, using in vivo multiphoton imaging to observe tangles and activation of executioner caspases in living tau transgenic mice (Tg4510 strain), we find the opposite: caspase activation occurs first, and precedes tangle formation by hours to days. New tangles form within a day. After a new tangle forms, the neuron remains alive and caspase activity seems to be suppressed. Similarly, introduction of wild-type 4-repeat tau (tau-4R) into wild-type animals triggered caspase activation, tau truncation and tau aggregation. Adeno-associated virus-mediated expression of a construct mimicking caspase-cleaved tau into wild-type mice led to the appearance of intracellular aggregates, tangle-related conformational- and phospho-epitopes, and the recruitment of full-length endogenous tau to the aggregates. On the basis of these data, we propose a new model in which caspase activation cleaves tau to initiate tangle formation, then truncated tau recruits normal tau to misfold and form tangles. Because tangle-bearing neurons are long-lived, we suggest that tangles are ‘off pathway’ to acute neuronal death. Soluble tau species, rather than fibrillar tau, may be the critical toxic moiety underlying neurodegeneration.
