被广泛接受的淀粉样蛋白假说，即在阿尔茨海默氏症中引起痴呆的神经异常，是淀粉样蛋白斑块几十年时间在脑中逐渐积累的结果。最近的一项发现表明，轴突缺陷可能发生在斑块形成之前，但通过利用活体多光子显微镜对阿尔茨海默氏症的一个小鼠模型中斑块形成进行跟踪所作的新的研究工作证实，淀粉样蛋白斑块的确是在局部神经毒性产生之前出现的。令人吃惊的是，这些斑块形成很快，可以在24小时内形成：一两天后，小胶质细胞进入，神经炎性变化就可以看到。有趣的是，这些观测结果提出这样一个可能性：阿尔茨海默氏症多年时间的神经退化会被皮质结构的突然变化中断，后者可能与这种疾病典型症状的变化相对应。
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: bhyman@partners.org).
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.
