The Role of SORL1 in Alzheimer's Disease

Genetic variation in SORL1 gene, also known as LR11, has been identified to associate with Alzheimer's disease (AD) through replicated genetic studies. As a type I transmembrane protein, SORL1 is composed of several distinct domains and belongs to both the low-density lipoprotein receptor (LDLR) family and the vacuolar protein sorting 10 (VPS10) domain receptor family. The level of SORL1 was found to be decreased in the AD brain which positively correlated with β-amyloid (Aβ) accumulation. Emerging data suggests that SORL1 contributes to AD through various pathways, including emerging as a central regulator of the trafficking and processing of amyloid precursor protein (APP), involvement in Aβ destruction, and interaction with ApoE and tau protein. Primarily, SORL1 interacts with distinct sets of cytosolic adaptors for anterograde and retrograde movement of APP between the trans-Golgi network (TGN) and early endosomes, thereby restricting the delivery of the precursor to endocytic compartments that favor amyloidogenic breakdown. In this article, we review recent epidemiological and genetical findings of SORL1 that related with AD and speculate the possible roles of SORL1 in the progression of this disease. Finally, given the potential contributions of SORL1 to AD pathogenesis, targeting SORL1 might present novel opportunities for AD therapy.