被廣泛接受的淀粉樣蛋白假說(shuō),，即在阿爾茨海默氏癥中引起癡呆的神經(jīng)異常，是淀粉樣蛋白斑塊幾十年時(shí)間在腦中逐漸積累的結(jié)果,。最近的一項(xiàng)發(fā)現(xiàn)表明,，軸突缺陷可能發(fā)生在斑塊形成之前，但通過(guò)利用活體多光子顯微鏡對(duì)阿爾茨海默氏癥的一個(gè)小鼠模型中斑塊形成進(jìn)行跟蹤所作的新的研究工作證實(shí),，淀粉樣蛋白斑塊的確是在局部神經(jīng)毒性產(chǎn)生之前出現(xiàn)的,。令人吃驚的是，這些斑塊形成很快,，可以在24小時(shí)內(nèi)形成：一兩天后,，小膠質(zhì)細(xì)胞進(jìn)入，神經(jīng)炎性變化就可以看到,。有趣的是,，這些觀測(cè)結(jié)果提出這樣一個(gè)可能性：阿爾茨海默氏癥多年時(shí)間的神經(jīng)退化會(huì)被皮質(zhì)結(jié)構(gòu)的突然變化中斷，后者可能與這種疾病典型癥狀的變化相對(duì)應(yīng),。
英文原文：
Nature 451, 720-724 (7 February 2008) | doi:10.1038/nature06616; Received 1 November 2007; Accepted 13 December 2007
Rapid appearance and local toxicity of amyloid- plaques in a mouse model of Alzheimer's disease
Melanie Meyer-Luehmann1, Tara L. Spires-Jones1, Claudia Prada1, Monica Garcia-Alloza1, Alix de Calignon1, Anete Rozkalne1, Jessica Koenigsknecht-Talboo2, David M. Holtzman2, Brian J. Bacskai1 & Bradley T. Hyman1
Alzheimer's Disease Research Laboratory, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA
Correspondence to: Bradley T. Hyman1 Correspondence and requests for materials should be addressed to B.T.H. (Email: [email protected]).
Abstract
Senile plaques accumulate over the course of decades in the brains of patients with Alzheimer's disease. A fundamental tenet of the amyloid hypothesis of Alzheimer's disease is that the deposition of amyloid- precedes and induces the neuronal abnormalities that underlie dementia1. This idea has been challenged, however, by the suggestion that alterations in axonal trafficking and morphological abnormalities precede and lead to senile plaques2. The role of microglia in accelerating or retarding these processes has been uncertain. To investigate the temporal relation between plaque formation and the changes in local neuritic architecture, we used longitudinal in vivo multiphoton microscopy to sequentially image young APPswe/PS1d9xYFP (B6C3-YFP) transgenic mice3. Here we show that plaques form extraordinarily quickly, over 24 h. Within 1–2 days of a new plaque's appearance, microglia are activated and recruited to the site. Progressive neuritic changes ensue, leading to increasingly dysmorphic neurites over the next days to weeks. These data establish plaques as a critical mediator of neuritic pathology.
