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Lysosomal sorting of amyloid-β by the SORLA receptor is impaired by a familial Alzheimer's disease mutation

Item Type:Article
Title:Lysosomal sorting of amyloid-β by the SORLA receptor is impaired by a familial Alzheimer's disease mutation
Creators Name:Caglayan, S. and Takagi-Niidome, S. and Liao, F. and Carlo, A.S. and Schmidt, V. and Burgert, T. and Kitago, Y. and Füchtbauer, E.M. and Füchtbauer, A. and Holtzman, D.M. and Takagi, J. and Willnow, T.E.
Abstract:SORLA/SORL1 is a unique neuronal sorting receptor for the amyloid precursor protein that has been causally implicated in both sporadic and autosomal dominant familial forms of Alzheimer's disease (AD). Brain concentrations of SORLA are inversely correlated with amyloid-{beta} (A{beta}) in mouse models and AD patients, suggesting that increasing expression of this receptor could be a therapeutic option for decreasing the amount of amyloidogenic products in affected individuals. We characterize a new mouse model in which SORLA is overexpressed, and show a decrease in A{beta} concentrations in mouse brain. We trace the underlying molecular mechanism to the ability of this receptor to direct lysosomal targeting of nascent A{beta} peptides. A{beta} binds to the amino-terminal VPS10P domain of SORLA, and this binding is impaired by a familial AD mutation in SORL1. Thus, loss of SORLA's A{beta} sorting function is a potential cause of AD in patients, and SORLA may be a new therapeutic target for AD drug development.
Keywords:Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animal Disease Models, Brain, Cell Line, LDL-Receptor Related Proteins, Lysosomes, Membrane Transport Proteins, Transgenic Mice, Animals, Mice
Source:Science Translational Medicine
ISSN:1946-6234
Publisher:American Association for the Advancement of Science (U.S.A.)
Volume:6
Number:223
Page Range:223ra20
Date:12 February 2014
Official Publication:https://doi.org/10.1126/scitranslmed.3007747
PubMed:View item in PubMed

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