Lysosomal Sorting of Amyloid-β by the SORLA Receptor Is Impaired by a Familial Alzheimer’s Disease Mutation
| Autor: | Vanessa Schmidt, Junichi Takagi, Thomas E. Willnow, Ernst-Martin Füchtbauer, Annette Füchtbauer, Fan Liao, Tilman Burgert, Safak Caglayan, Shizuka Takagi-Niidome, Anne-Sophie Carlo, David M. Holtzman, Yu Kitago |
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| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_specialty
Transgene SORL1 Mice Transgenic Biology medicine.disease_cause Cell Line Amyloid beta-Protein Precursor Mice Alzheimer Disease Internal medicine medicine Amyloid precursor protein Animals Humans Receptor LDL-Receptor Related Proteins Mutation Amyloid beta-Peptides Brain Membrane Transport Proteins General Medicine Cell biology Disease Models Animal Endocrinology Drug development Cell culture biology.protein Lysosomes Function (biology) |
| Zdroj: | Science Translational Medicine. 6 |
| ISSN: | 1946-6242 1946-6234 |
| DOI: | 10.1126/scitranslmed.3007747 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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