Elevated levels of Secreted-Frizzled-Related-Protein 1 contribute to Alzheimer's disease pathogenesis
Elevated levels of Secreted-Frizzled-Related-Protein 1 contribute to Alzheimer's disease pathogenesis
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DOI：
10.1038/s41593-019-0432-1
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发表时间：
2019-08-01
影响因子：
25
通讯作者：
Bovolenta, Paola
中科院分区：
文献类型：
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作者：
Esteve, Pilar;Rueda-Carrasco, Javier;Bovolenta, Paola
淀粉样β肽的聚集沉积是阿尔茨海默病（AD）的特征性特征，淀粉样β肽来源于淀粉样β蛋白（APP）的促淀粉样蛋白生成加工（pro-amyloidogenic processing）成特征性淀粉样斑块（AP）。通过金属蛋白酶ADAM 10的替代APP加工防止淀粉样蛋白-β形成。我们测试了是否ADAM 10活性的下调，其分泌的内源性抑制剂分泌卷曲相关蛋白1（SFRP 1）是散发性AD的一个共同特征。我们证明，SFRP 1在AD患者的脑和脑脊液中显著增加，在AP中积累并与淀粉样蛋白β结合，阻碍淀粉样蛋白β原纤维形成。Sfrp 1在AD样小鼠模型中的过表达预期AP和营养不良性神经突的出现，而其遗传失活或α-SFRP 1中和抗体的输注有利于非淀粉样蛋白生成的APP加工。Sfrp 1功能下降降低AP积累，改善AD相关的组织病理学特征，并防止长时程增强丧失和认知缺陷。我们的研究揭示了SFRP 1在AD发病机制中的重要作用和有希望的AD治疗靶点。
The deposition of aggregated amyloid-beta peptides derived from the pro-amyloidogenic processing of the amyloid precurson protein (APP) into characteristic amyloid plaques (APs) is distinctive to Alzheimer's disease (AD). Alternative APP processing via the metalloprotease ADAM10 prevents amyloid-beta formation. We tested whether downregulation of ADAM10 activity by its secreted endogenous inhibitor secreted-frizzled-related protein 1 (SFRP1) is a common trait of sporadic AD. We demonstrate that SFRP1 is significantly increased in the brain and cerebrospinal fluid of patients with AD, accumulates in APs and binds to amyloid-beta, hindering amyloid-beta protofibril formation. Sfrp1 overexpression in an AD-like mouse model anticipates the appearance of APs and dystrophic neurites, whereas its genetic inactivation or the infusion of alpha-SFRP1-neutralizing antibodies favors non-amyloidogenic APP processing. Decreased Sfrp1 function lowers AP accumulation, improves AD-related histopathological traits and prevents long-term potentiation loss and cognitive deficits. Our study unveils SFRP1 as a crucial player in AD pathogenesis and a promising AD therapeutic target.