RT Journal Article
SR Electronic
T1 Lysosomal Sorting of Amyloid-β by the SORLA Receptor Is Impaired by a Familial Alzheimer’s Disease Mutation
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP 223ra20
OP 223ra20
DO 10.1126/scitranslmed.3007747
VO 6
IS 223
A1 Caglayan, Safak
A1 Takagi-Niidome, Shizuka
A1 Liao, Fan
A1 Carlo, Anne-Sophie
A1 Schmidt, Vanessa
A1 Burgert, Tilman
A1 Kitago, Yu
A1 Füchtbauer, Ernst-Martin
A1 Füchtbauer, Annette
A1 Holtzman, David M.
A1 Takagi, Junichi
A1 Willnow, Thomas E.
YR 2014
UL http://stm.sciencemag.org/content/6/223/223ra20.abstract
AB 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.