Abstract
Proteolytic cleavage in the ectodomain of the amyloid precursor protein (APP) is a key regulatory step in the generation of the Alzheimer's disease amyloid-beta (A beta) pepticle and occurs through two different protease activities termed alpha- and beta-secretase. Both proteases compete for APP cleavage, but have opposite effects on A beta generation. At present, little is known about the cellular pathways that control APP alpha- or beta-secretase cleavage and thus A beta generation. To explore the contributory pathways in more detail we have recently employed an expression cloning screen and identified several activators of APP cleavage by alpha- or beta-secretase. Among them were known activators of APP cleavage, for example protein kinase A, and novel activators, such as endophilin and the APP homolog amyloid precursor-like protein 1 (APLP1). Mechanistic analysis revealed that both endophilin and APLP1 reduce the rate of APP endocytosis and strongly increase APP cleavage by alpha-secretase. This review summarizes the results of the expression cloning screen in the context of recent developments in our understanding of the cellular regulation of APP alpha-secretase cleavage. Moreover, it highlights the particular importance of endocytic APP trafficking as a prime modulator of APP shedding. Copyright (c) 2006 S. Karger AG, Basel.
| Item Type: | Journal article |
|---|---|
| Form of publication: | Publisher's Version |
| Faculties: | Medicine |
| Subjects: | 600 Technology > 610 Medicine and health |
| URN: | urn:nbn:de:bvb:19-epub-16591-1 |
| ISSN: | 1660-2854 |
| Alliance/National Licence: | This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. |
| Language: | English |
| Item ID: | 16591 |
| Date Deposited: | 29. Aug 2013 09:59 |
| Last Modified: | 04. Nov 2020 12:58 |
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