title: 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.
authors: Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany.
authors: Safak
authors: S
authors: Caglayan
authors: Shizuka
authors: S
authors: Takagi-Niidome
authors: Fan
authors: F
authors: Liao
authors: Anne-Sophie
authors: AS
authors: Carlo
authors: Vanessa
authors: V
authors: Schmidt
authors: Tilman
authors: T
authors: Burgert
authors: Yu
authors: Y
authors: Kitago
authors: Ernst-Martin
authors: EM
authors: Füchtbauer
authors: Annette
authors: A
authors: Füchtbauer
authors: David M
authors: DM
authors: Holtzman
authors: Junichi
authors: J
authors: Takagi
authors: Thomas E
authors: TE
authors: Willnow
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; C102582:SORL1 protein, human