Sialylation enhances the secretion of neurotoxic amyloid-β peptides
Sialylation enhances the secretion of neurotoxic amyloid-β peptides
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DOI：
10.1111/j.1471-4159.2005.03595.x
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发表时间：
2006-02-01
影响因子：
4.7
通讯作者：
Hashimoto, Y
中科院分区：
文献类型：
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作者：
Nakagawa, K;Kitazume, S;Hashimoto, Y
阿尔茨海默病（AD）的特征是淀粉样蛋白- β肽（A β）在大脑中的沉积。β是由β分泌酶（BACE1: β位点APP切割酶1）和γ分泌酶连续切割淀粉样蛋白前体蛋白（APP）产生的。先前，我们证明BACE1也切割β -半乳糖α 2,6-唾液转移酶（ST6Gal-I）并下调其转移酶活性。在这里，我们报道了ST6Gal-I在Neuro2a细胞中的过表达增强了内源性APP的α 2,6-唾液化，并将其代谢产物A β的细胞外水平提高了2倍，可溶性APP β (sAPP β)提高了3倍，sAPP α提高了2.5倍)。唾液酸缺失突变（Lec-2）细胞分泌的A β是野生型中国仓鼠卵巢（CHO）细胞的一半。此外，野生型CHO细胞在ST6Gal-I过表达时，APP代谢物的分泌增强，而lec2细胞则没有，这表明分泌增强需要细胞蛋白的唾液化。缺乏n -糖基化位点的突变体APP （APP- asn467,496ala）的代谢物分泌在ST6Gal-I过表达后没有增强，这表明APP本身的n -聚糖是增强分泌所必需的。在小鼠大脑中，α 2,6-唾液化APP的数量似乎与sAPP β水平相关。这些结果表明APP的唾液化可促进其代谢转化，并可能影响AD的病理。
Alzheimer's disease (AD) is characterized by amyloid-beta peptide (A beta) deposition in the brain. A beta is produced by sequential cleavage of amyloid precursor protein (APP) by beta-secretase (BACE1: beta-site APP-cleaving enzyme 1) and gamma-secretase. Previously, we demonstrated that BACE1 also cleaves beta-galactoside alpha 2,6-sialyltransferase (ST6Gal-I) and down-regulates its transferase activity. Here, we report that overexpression of ST6Gal-I in Neuro2a cells enhanced alpha 2,6-sialylation of endogenous APP and increased the extracellular levels of its metabolites A beta by two-fold, soluble APP beta (sAPP beta) by three-fold and sAPP alpha by 2.5-fold). Sialylation-deficient mutant (Lec-2) cells secreted half as much A beta as wild-type Chinese hamster ovary (CHO) cells. Furthermore, wild-type CHO cells showed enhanced secretion of the APP metabolites upon ST6Gal-I overexpression, whereas Lec-2 cells did not, indicating that the secretion enhancement requires sialylation of cellular protein(s). Secretion of metabolites from a mutant APP (APP-Asn467,496Ala) that lacked N-glycosylation sites was not enhanced upon ST6Gal-I overexpression, suggesting that the N-glycans on APP itself are required for the enhanced secretion. In the mouse brain, the amount of alpha 2,6-sialylated APP appeared to be correlated with the sAPP beta level. These results suggest that sialylation of APP promotes its metabolic turnover and could affect the pathology of AD.