Brain oligomeric β-amyloid but not total amyloid plaque burden correlates with neuronal loss and astrocyte inflammatory response in amyloid precursor protein/tau transgenic mice.
Brain oligomeric β-amyloid but not total amyloid plaque burden correlates with neuronal loss and astrocyte inflammatory response in amyloid precursor protein/tau transgenic mice.
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DOI：
10.1097/nen.0b013e318217a118
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发表时间：
2011-05
影响因子：
3.2
通讯作者：
Gómez-Isla T
中科院分区：
文献类型：
--
作者：
DaRocha-Souto B;Scotton TC;Coma M;Serrano-Pozo A;Hashimoto T;Serenó L;Rodríguez M;Sánchez B;Hyman BT;Gómez-Isla T
长期以来，人们一直认为β-淀粉样蛋白（Aβ）必须组装成纤维状淀粉样蛋白斑块才能在阿尔茨海默病中发挥其神经毒性作用。另一种假设是Aβ的可溶性寡聚体在神经元损伤中的作用比不溶性组分大得多。我们通过研究17月龄的双转基因APPsw-tauvlw小鼠脑中寡聚Aβ种类和经典纤维状淀粉样斑块的临床病理学相关性，在体内测试了这些竞争性假设。脑寡聚体Aβ的生化和免疫组织化学测量值随年龄呈指数增加。寡聚体Aβ负荷与纤维状Aβ沉积的形态学标志物相关。与总淀粉样斑块负荷相反，构象表位特异性抗体Nab 61标记的寡聚Aβ沉积物的量与内嗅皮质和CA 1海马子区的神经元损失和星形胶质细胞数量密切相关。然而，与其他形态学Aβ测量结果一样，脑寡聚体Aβ负荷与这些小鼠的记忆缺陷没有很好的相关性。内嗅皮层和CA 1区胶质酸性蛋白阳性星形胶质细胞的数量与记忆障碍和神经元细胞丢失密切相关。基于这些发现，我们假设星形胶质细胞反应（可能由脑寡聚体Aβ蓄积触发）对认知产生不利影响，并且也可能导致该模型中的神经元细胞死亡。
It has long been assumed that β-amyloid (Aβ) had to assemble into fibrillar amyloid plaques to exert its neurotoxic effects in Alzheimer disease. An alternative hypothesis is that soluble oligomers of Aβ play a much larger role in neuronal damage than the insoluble component. We have tested these competing hypotheses in vivo by studying the clinicopathologic correlates of oligomeric Aβ species and classic fibrillar amyloid plaques in the brains of double-transgenic APPsw-tauvlw mice up to 17 months of age. Biochemical and immunohistochemical measures of brain oligomeric Aβ exponentially increased with age. Oligomeric Aβ load correlated with morphological markers of fibrillar Aβ deposition. In contrast to total amyloid plaque burden, the amount of oligomeric Aβ deposits labeled by the con-formational epitope-specific antibody Nab61 closely correlated with neuronal loss and numbers of astrocytes in the entorhinal cortex and the CA1 hippocampal subfield. However, like other morphological Aβ measurements, brain oligomeric Aβ burden did not correlate well with memory deficits in these mice. The number of glial fibrillary acidic protein–positive astrocytes in entorhinal cortex and CA1 most tightly correlated with memory impairment and neuronal cell loss. Based on these findings, we hypothesize that the astrocyte response, which is likely triggered by brain oligomeric Aβ accumulation, adversely affects cognition and might also contribute to neuronal cell death in this model.