γ-Secretase Component Presenilin Is Important for Microglia β-Amyloid Clearance
γ-Secretase Component Presenilin Is Important for Microglia β-Amyloid Clearance
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DOI：
10.1002/ana.22191
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发表时间：
2011-01-01
影响因子：
11.2
通讯作者：
Frenkel, Dan
中科院分区：
文献类型：
--
作者：
Farfara, Dorit;Trudler, Dorit;Frenkel, Dan
目的：γ-分泌酶对淀粉样前体蛋白的裂解是阿尔茨海默病发病机制的一个重要方面。 γ-分泌酶还裂解其他控制细胞发育和稳态的膜蛋白（例如Notch）。早老素 1 和 2 被认为是γ-分泌酶催化位点的重要决定因素。我们的目的是研究γ-分泌酶是否对小胶质细胞吞噬阿尔茨海默病β-淀粉样蛋白很重要。方法：我们使用γ-分泌酶抑制剂、小发夹RNA和早老素缺陷小鼠，研究了细胞培养物中γ-分泌酶在小胶质细胞对β-淀粉样蛋白吞噬活性中的作用。结果：我们发现γ-分泌酶抑制剂会损害小胶质细胞的基因表达、蛋白质活性水平和迁移能力，导致可溶性β-淀粉样蛋白吞噬作用减少。此外，缺乏早老蛋白1和2的小胶质细胞对可溶性β-淀粉样蛋白的吞噬作用受到损害。与野生型小鼠的小胶质细胞相比，γ-分泌酶催化位点的功能障碍导致从阿尔茨海默病小鼠模型的脑切片中清除不溶性β-淀粉样蛋白的能力受损。解释：我们首次提出γ-分泌酶在阿尔茨海默病中的双重作用。一个作用是裂解淀粉样蛋白前体蛋白以产生病理性β-淀粉样蛋白，另一个作用是调节小胶质细胞活性，这对于清除神经毒性β-淀粉样蛋白沉积物非常重要。对小胶质细胞中γ-分泌酶介导的细胞途径的进一步研究可能为阿尔茨海默病和其他神经退行性疾病的发展提供有用的见解，为未来的治疗干预提供途径。安神经学 2011；69:170-180
Objective: The cleavage of amyloid precursor protein by gamma-secretase is an important aspect of the pathogenesis of Alzheimer's disease. gamma-Secretase also cleaves other membrane proteins (eg, Notch), which control cell development and homeostasis. Presenilin 1 and 2 are considered important determinants of the gamma-secretase catalytic site. Our aim was to investigate whether gamma-secretase can be important for microglial phagocytosis of Alzheimer's disease beta-amyloid.Methods: We investigated the role of gamma-secretase in microglia activity toward beta-amyloid phagocytosis in cell culture using gamma-secretase inhibitors and small hairpin RNA and presenilin-deficient mice.Results: We found that gamma-secretase inhibitors impair microglial activity as measured in gene expression, protein levels, and migration ability, which resulted in a reduction of soluble beta-amyloid phagocytosis. Moreover, microglia deficient in presenilin 1 and 2 showed impairment in phagocytosis of soluble beta-amyloid. Dysfunction in the gamma-secretase catalytic site led to an impairment in clearing insoluble beta-amyloid from brain sections taken from an Alzheimer's disease mouse model when compared to microglia from wild-type mice.Interpretation: We suggest for the first time, a dual role for gamma-secretase in Alzheimer's disease. One role is the cleavage of the amyloid precursor protein for pathologic beta-amyloid production and the other is to regulate microglia activity that is important for clearing neurotoxic beta-amyloid deposits. Further studies of gamma-secretase-mediated cellular pathways in microglia may provide useful insights into the development of Alzheimer's disease and other neurodegenerative diseases, providing future avenues for therapeutic intervention. ANN NEUROL 2011;69:170-180