Rutten Bart P F, Van der Kolk Nicolien M, Schafer Stephanie, van Zandvoort Marc A M J, Bayer Thomas A, Steinbusch Harry W M, Schmitz Christoph
Division Cellular Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
Am J Pathol. 2005 Jul;167(1):161-73. doi: 10.1016/S0002-9440(10)62963-X.
Neuron and synapse loss are important features of the neuropathology of Alzheimer's disease (AD). Recently, we observed substantial age-related hippocampal neuron loss in APP751SL/PS1M146L transgenic mice but not in PS1M146L mice. Here, we investigated APP751SL mice, PS1M146L mice, and APP751SL/PS1M146L mice for age-related alterations in synaptic integrity within hippocampal stratum moleculare of the dentate gyrus (SM), stratum lucidum of area CA3 (SL), and stratum radiatum of area CA1-2 (SR) by analyzing densities and numbers of synaptophysin-immunoreactive presynaptic boutons (SIPBs). Wild-type mice, APP751SL mice and PS1M146L mice showed similar amounts of age-related SIPB loss within SM, and no SIPB loss within SL. Both APP751SL mice and PS1M146L mice showed age-related SIPB loss within SR. Importantly, APP751SL/PS1M146L) mice displayed the severest age-related SIPB loss within SM, SL, and SR, even in regions free of extracellular Abeta deposits. Together, these mouse models offer a unique framework to study the impact of several molecular and cellular events caused by mutant APP and/or mutant PS1 on age-related alterations in synaptic integrity. The observation of age-related SIPB loss within SR of PS1M146L mice supports a role of mutant PS1 in neurodegeneration apart from its contribution to alterations in Abeta generation.
神经元和突触丧失是阿尔茨海默病(AD)神经病理学的重要特征。最近,我们观察到APP751SL/PS1M146L转基因小鼠出现了与年龄相关的大量海马神经元丧失,而PS1M146L小鼠未出现这种情况。在此,我们通过分析突触素免疫反应性突触前终扣(SIPB)的密度和数量,研究了APP751SL小鼠、PS1M146L小鼠以及APP751SL/PS1M146L小鼠在齿状回分子层(SM)、CA3区透明层(SL)和CA1-2区辐射层(SR)内与年龄相关的突触完整性变化。野生型小鼠、APP751SL小鼠和PS1M146L小鼠在SM内与年龄相关的SIPB丧失量相似,在SL内未出现SIPB丧失。APP751SL小鼠和PS1M146L小鼠在SR内均出现了与年龄相关的SIPB丧失。重要的是,APP751SL/PS1M146L小鼠在SM、SL和SR内表现出最严重的与年龄相关的SIPB丧失,即使在没有细胞外β淀粉样蛋白沉积的区域也是如此。总之,这些小鼠模型提供了一个独特的框架,用于研究由突变型APP和/或突变型PS1引起的多种分子和细胞事件对与年龄相关的突触完整性变化的影响。在PS1M146L小鼠的SR内观察到与年龄相关的SIPB丧失,这支持了突变型PS1在神经退行性变中的作用,除了其对β淀粉样蛋白生成改变的影响之外。