| First Author | Caglayan S | Year | 2014 |
| Journal | Sci Transl Med | Volume | 6 |
| Issue | 223 | Pages | 223ra20 |
| PubMed ID | 24523320 | Mgi Jnum | J:213687 |
| Mgi Id | MGI:5585578 | Doi | 10.1126/scitranslmed.3007747 |
| Citation | Caglayan S, et al. (2014) Lysosomal sorting of amyloid-beta by the SORLA receptor is impaired by a familial Alzheimer's disease mutation. Sci Transl Med 6(223):223ra20 |
| abstractText | 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 (Abeta) 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 Abeta concentrations in mouse brain. We trace the underlying molecular mechanism to the ability of this receptor to direct lysosomal targeting of nascent Abeta peptides. Abeta 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 Abeta sorting function is a potential cause of AD in patients, and SORLA may be a new therapeutic target for AD drug development. |
