Sequences from the low density lipoprotein receptor-related protein (LRP) cytoplasmic domain enhance amyloid β protein production via the β-secretase pathway without altering amyloid precursor protein/LRP nuclear signaling

被引:32
作者
Yoon, IS [1 ]
Pietrzik, CU [1 ]
Kang, DE [1 ]
Koo, EH [1 ]
机构
[1] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA
关键词
D O I
10.1074/jbc.M413729200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Increasing evidence suggests that the low density lipoprotein receptor-related protein (LRP) affects the processing of amyloid precursor protein (APP) and amyloid beta (A beta) protein production as well as mediates the clearance of A beta from the brain. Recent studies indicate that the cytoplasmic domain of LRP is critical for this modulation of APP processing requiring perhaps a complex between APP, the adaptor protein FE65, and LRP. In this study, we expressed a small LRP domain consisting of the C-terminal 97 amino acids of the cytoplasmic domain, or LRP-soluble tail (LRP-ST), in CHO cells to test the hypothesis that the APP(.)LRP complex can be disrupted. We anticipated that LRP-ST would inhibit the normal interaction between LRP and APP and therefore perturb APP processing to resemble a LRP-deficient state. Surprisingly, CHO cells expressing LRP-ST demonstrated an increase in both sAPP secretion and A beta production compared with control CHO cells in a manner reminiscent of the cellular effects of the APP "Swedish mutation." The increase in sAPP secretion consisted mainly of sAPP beta, consistent with the increase in A beta release. Further, this effect is LRP-independent, as the same alterations remained when LRP-ST was expressed in LRP-deficient cells but not when the construct was membrane-anchored. Finally, deletion experiments suggested that the last 50 amino acid residues of LRP-ST contain the important domain for altering APP processing and A beta production. These observations indicate that there are cellular pathways that may suppress A beta generation but that can be altered to facilitate A beta production.
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页码:20140 / 20147
页数:8
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