Schmitz Christoph, Rutten Bart P F, Pielen Andrea, Schäfer Stephanie, Wirths Oliver, Tremp Günter, Czech Christian, Blanchard Veronique, Multhaup Gerd, Rezaie Payam, Korr Hubert, Steinbusch Harry W M, Pradier Laurent, Bayer Thomas A
Department of Psychiatry and Neuropsychology, Division of Cellular Neuroscience, University of Maastricht, Maastricht, The Netherlands.
Am J Pathol. 2004 Apr;164(4):1495-502. doi: 10.1016/S0002-9440(10)63235-X.
According to the "amyloid hypothesis of Alzheimer's disease," beta-amyloid is the primary driving force in Alzheimer's disease pathogenesis. Despite the development of many transgenic mouse lines developing abundant beta-amyloid-containing plaques in the brain, the actual link between amyloid plaques and neuron loss has not been clearly established, as reports on neuron loss in these models have remained controversial. We investigated transgenic mice expressing human mutant amyloid precursor protein APP751 (KM670/671NL and V717I) and human mutant presenilin-1 (PS-1 M146L). Stereologic and image analyses revealed substantial age-related neuron loss in the hippocampal pyramidal cell layer of APP/PS-1 double-transgenic mice. The loss of neurons was observed at sites of Abeta aggregation and surrounding astrocytes but, most importantly, was also clearly observed in areas of the parenchyma distant from plaques. These findings point to the potential involvement of more than one mechanism in hippocampal neuron loss in this APP/PS-1 double-transgenic mouse model of Alzheimer's disease.
根据“阿尔茨海默病的淀粉样蛋白假说”，β-淀粉样蛋白是阿尔茨海默病发病机制的主要驱动力。尽管已经培育出许多在大脑中形成大量含β-淀粉样蛋白斑块的转基因小鼠品系，但淀粉样斑块与神经元丢失之间的实际联系尚未明确建立，因为这些模型中关于神经元丢失的报道仍存在争议。我们研究了表达人类突变淀粉样前体蛋白APP751（KM670/671NL和V717I）和人类突变早老素-1（PS-1 M146L）的转基因小鼠。体视学和图像分析显示，APP/PS-1双转基因小鼠海马锥体细胞层存在大量与年龄相关的神经元丢失。在Aβ聚集部位和周围星形胶质细胞处观察到神经元丢失，但最重要的是，在远离斑块的实质区域也明显观察到神经元丢失。这些发现表明，在这种阿尔茨海默病的APP/PS-1双转基因小鼠模型中，海马神经元丢失可能涉及多种机制。
