Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease

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-β 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. To explore the formation of amyloid plaques and to determine the effects of newly formed dense-cored plaques on the microarchitecture of the brain, we have developed a novel in vivo multiphoton imaging technique. This recognizes newly formed plaques and allows monitoring of their immediate vicinity thereafter to determine the rate of their formation and the temporal sequence of pathophysiological events. We imaged young (5to 6-month-old) B6C3-YFP mice, an age when plaques begin to appear4 (Fig. 1). We used three-colour imaging to establish fiduciary markers for repeated imaging: YFP positive neurons, dendrites and axons in the cortex, methoxy-XO4-labelled fibrillar amyloid-β deposits in the parenchyma and on vessel walls, and a fluorescent angiogram with Texas red dextran to image blood vessels. A volume of cortex (lamina I–III) that initially did not contain plaques was re-imaged until repeat imaging detected a new plaque, establishing its ‘birthday’. To ensure that the appearance of a new plaque did not simply reflect a greater depth of imaging or a slightly different imaging volume, we went through each image stack and compared © 2008 Nature Publishing Group Correspondence and requests for materials should be, addressed to B.T.H. ([email protected]). Supplementary Information is linked to the online version of the paper at www.nature.com/nature. Author Contributions M.M.-L. and B.T.H. designed the study; M.M.-L., T.L.S.-J., C.P., M.G.-A., A.de C. and A.R. performed experiments; J.K.-T. and D.M.H. provided mice; M.M.-L. and B.T.H. wrote the manuscript; B.J.B. gave technical support and conceptual advice; B.T.H. supervised the study. NIH Public Access