Abstract：
Alzheimer\'s disease (AD) is a complex neurodegenerative disorder that develops over decades. AD brain proteomics reveals vast alterations in protein levels and numerous altered biologic pathways. Here, we compare AD brain proteome and network changes with the brain proteomes of amyloid β (Aβ)-depositing mice to identify conserved and divergent protein networks with the conserved networks identifying an Aβ amyloid responsome. Proteins in the most conserved network (M42) accumulate in plaques, cerebrovascular amyloid (CAA), and/or dystrophic neuronal processes, and overexpression of two M42 proteins, midkine (Mdk) and pleiotrophin (PTN), increases the accumulation of Aβ in plaques and CAA. M42 proteins bind amyloid fibrils in vitro, and MDK and PTN co-accumulate with cardiac transthyretin amyloid. M42 proteins appear intimately linked to amyloid deposition and can regulate amyloid deposition, suggesting that they are pathology modifiers and thus putative therapeutic targets. We posit that amyloid-scaffolded accumulation of numerous M42+ proteins is a central mechanism mediating downstream pathophysiology in AD.
摘要：
阿尔茨海默病（AD）是一种复杂的神经退行性疾病，发展了几十年。AD脑蛋白质组学揭示了蛋白质水平的巨大改变和许多改变的生物学途径。这里,我们将AD脑蛋白质组和网络变化与淀粉样蛋白β(Aβ)沉积小鼠的脑蛋白质组进行比较,以鉴定保守和不同的蛋白质网络,以及鉴定Aβ淀粉样蛋白反应体的保守网络.最保守网络（M42）中的蛋白质在斑块中积累，脑血管淀粉样蛋白（CAA），和/或营养不良的神经元过程，和两种M42蛋白的过表达，中期因子（Mdk）和多效蛋白（PTN），增加Aβ在斑块和CAA中的积累。M42蛋白在体外结合淀粉样纤维，MDK和PTN与心脏甲状腺素运载蛋白淀粉样蛋白共同积累。M42蛋白似乎与淀粉样蛋白沉积密切相关，可以调节淀粉样蛋白沉积，表明它们是病理修饰剂，因此是推定的治疗靶标。我们认为，许多M42蛋白的淀粉样蛋白支架状积累是介导AD下游病理生理学的核心机制。
