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

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 Aβ peptides. Aβ 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.

journal_name

Sci Transl Med

authors

Caglayan S,Takagi-Niidome S,Liao F,Carlo AS,Schmidt V,Burgert T,Kitago Y,Füchtbauer EM,Füchtbauer A,Holtzman DM,Takagi J,Willnow TE

doi

10.1126/scitranslmed.3007747

subject

Has Abstract

pub_date

2014-02-12 00:00:00

pages

223ra20

issue

223

eissn

1946-6234

issn

1946-6242

pii

6/223/223ra20

journal_volume

6

pub_type

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