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

Official URL:https://doi.org/10.1126/scitranslmed.3007747
PubMed:View item in PubMed
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 Fuechtbauer, E.M. and Fuechtbauer, A. and Holtzman, D.M. and Takagi, J. and Willnow, T.E.
Journal Title:Science Translational Medicine
Journal Abbreviation:Sci Transl Med
Page Range:223ra20
Date:12 February 2014
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
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.
Publisher:American Association for the Advancement of Science (U.S.A.)
Item Type:Article

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