Acta Neuropathol Commun. 2014 Jun 29;2:76. doi: 10.1186/s40478-014-0076-z.
Alzheimer's disease is caused by increased production or reduced clearance of amyloid-β, which results in the formation amyloid-β plaques and triggers a cascade of downstream events leading to progressive neurodegeneration. The earliest clinical symptoms of Alzheimer's disease, i.e., memory loss, are however poorly understood from a molecular and cellular perspective. Here we used APPswe/PS1dE9 (APP/PS1) transgenic mice to study the early pre-pathological effects of increased amyloid-β levels on hippocampal synaptic plasticity and memory. Using an unbiased proteomics approach we show that the early increase in amyloid-β levels in APP/PS1 mice at three months of age coincides with a robust and significant upregulation of several protein components of the extracellular matrix in hippocampal synaptosome preparations. This increase in extracellular matrix levels occurred well before the onset of plaque formation and was paralleled by impairments in hippocampal long-term potentiation and contextual memory. Direct injection into the hippocampus of the extracellular matrix inactivating enzyme chondroitinase ABC restored both long-term potentiation and contextual memory performance. These findings indicate an important role for the extracellular matrix in causing early memory loss in Alzheimer's disease.
阿尔茨海默病是由淀粉样蛋白-β的产生增加或清除减少引起的，这导致淀粉样蛋白-β斑块的形成，并引发一系列下游事件，导致进行性神经退行性变。然而，从分子和细胞的角度来看，阿尔茨海默病的最早临床症状，即记忆丧失，还不太清楚。在这里，我们使用 APPswe/PS1dE9 (APP/PS1) 转基因小鼠来研究淀粉样蛋白-β水平升高对海马突触可塑性和记忆的早期预病理影响。使用无偏蛋白质组学方法，我们表明，APP/PS1 小鼠在三个月大时淀粉样蛋白-β水平的早期增加与海马突触体制剂中细胞外基质的几个蛋白质成分的显著上调一致。这种细胞外基质水平的增加发生在斑块形成之前，并且伴随着海马体长时程增强和情境记忆的损伤。直接将细胞外基质失活酶软骨素酶 ABC 注射到海马体中，可恢复长时程增强和情境记忆的表现。这些发现表明细胞外基质在导致阿尔茨海默病早期记忆丧失方面起着重要作用。
