Phinney A L, Deller T, Stalder M, Calhoun M E, Frotscher M, Sommer B, Staufenbiel M, Jucker M
Department of Neuropathology, Institute of Pathology, University of Basel, CH-4003 Basel, Switzerland.
J Neurosci. 1999 Oct 1;19(19):8552-9. doi: 10.1523/JNEUROSCI.19-19-08552.1999.
A characteristic feature of Alzheimer's disease (AD) is the formation of amyloid plaques in the brain. Although this hallmark pathology has been well described, the biological effects of plaques are poorly understood. To study the effect of amyloid plaques on axons and neuronal connectivity, we have examined the axonal projections from the entorhinal cortex in aged amyloid precursor protein (APP) transgenic mice that exhibit cerebral amyloid deposition in plaques and vessels (APP23 mice). Here we report that entorhinal axons form dystrophic boutons around amyloid plaques in the entorhinal termination zone of the hippocampus. More importantly, entorhinal boutons were found associated with amyloid in ectopic locations within the hippocampus, the thalamus, white matter tracts, as well as surrounding vascular amyloid. Many of these ectopic entorhinal boutons were immunopositive for the growth-associated protein GAP-43 and showed light and electron microscopic characteristics of axonal terminals. Our findings suggest that (1) cerebral amyloid deposition has neurotropic effects and is the main cause of aberrant sprouting in AD brain; (2) the magnitude and significance of sprouting in AD have been underestimated; and (3) cerebral amyloid leads to the disruption of neuronal connectivity which, in turn, may significantly contribute to AD dementia.
阿尔茨海默病（AD）的一个特征性表现是大脑中淀粉样斑块的形成。尽管这种标志性病理特征已得到充分描述，但斑块的生物学效应却知之甚少。为了研究淀粉样斑块对轴突和神经元连接的影响，我们检测了老年淀粉样前体蛋白（APP）转基因小鼠内嗅皮质的轴突投射，这些小鼠在斑块和血管中出现脑淀粉样沉积（APP23小鼠）。我们在此报告，在内嗅皮质在海马的终末区内，内嗅轴突在淀粉样斑块周围形成营养不良性终扣。更重要的是，在内嗅终扣在海马、丘脑、白质束内的异位位置以及周围血管淀粉样物中发现与淀粉样物相关。许多这些异位内嗅终扣对生长相关蛋白GAP - 43呈免疫阳性，并表现出轴突终末的光镜和电镜特征。我们的研究结果表明：（1）脑淀粉样沉积具有神经趋向性作用，是AD脑内异常发芽的主要原因；（2）AD中发芽的程度和意义被低估了；（3）脑淀粉样物导致神经元连接的破坏，进而可能显著促成AD痴呆。
