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

Safak Caglayan, Shizuka Takagi-Niidome, Fan Liao, Anne Sophie Carlo, Vanessa Schmidt, Tilman Burgert, Yu Kitago, Ernst Martin Fuc̈htbauer, Annette Fuc̈htbauer, David M. Holtzman, Junichi Takagi, Thomas E. Willnow

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

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-β (Aβ) 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 Aβ concentrations in mouse brain. We trace the underlying molecular mechanism to the ability of this receptor to direct lysosomal targeting of nascent Ab peptides. Ab 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 Aβ sorting function is a potential cause of AD in patients, and SORLA may be a new therapeutic target for AD drug development.

Original languageEnglish
Article number223ra20
JournalScience translational medicine
Volume6
Issue number223
DOIs
StatePublished - Feb 12 2014

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