title: LRAD3, a novel low-density lipoprotein receptor family member that modulates amyloid precursor protein trafficking.
abstract: We have identified a novel low-density lipoprotein (LDL) receptor family member, termed LDL receptor class A domain containing 3 (LRAD3), which is expressed in neurons. The LRAD3 gene encodes an ∼50 kDa type I transmembrane receptor with an ectodomain containing three LDLa repeats, a transmembrane domain, and a cytoplasmic domain containing a conserved dileucine internalization motif and two polyproline motifs with potential to interact with WW-domain-containing proteins. Immunohistochemical analysis of mouse brain reveals LRAD3 expression in the cortex and hippocampus. In the mouse hippocampal-derived cell line HT22, LRAD3 partially colocalizes with amyloid precursor protein (APP) and interacts with APP as revealed by coimmunoprecipitation experiments. To identify the portion of APP that interacts with LRAD3, we used solid-phase binding assays that demonstrated that LRAD3 failed to bind to a soluble APP fragment (sAPPα) released after α-secretase cleavage. In contrast, C99, the β-secretase product that remains cell associated, coprecipitated with LRAD3, confirming that regions within this portion of APP are important for associating with LRAD3. The association of LRAD3 with APP increases the amyloidogenic pathway of APP processing, resulting in a decrease in sAPPα production and increased Aβ peptide production. Pulse-chase experiments confirm that LRAD3 expression significantly decreases the cellular half-life of mature APP. These results reveal that LRAD3 influences APP processing and raises the possibility that LRAD3 alters APP function in neurons, including its downstream signaling.
authors.affiliation: Center for Vascular and Inflammatory Diseases and the Departments of Surgery and Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Sripriya
authors.initials: S
authors.lastname: Ranganathan
authors.forename: Nathaniel C
authors.initials: NC
authors.lastname: Noyes
authors.forename: Mary
authors.initials: M
authors.lastname: Migliorini
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Winkles
authors.forename: Frances D
authors.initials: FD
authors.lastname: Battey
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Smith
authors.forename: Manuel
authors.initials: M
authors.lastname: Yepes
authors.forename: Irina
authors.initials: I
authors.lastname: Mikhailenko
authors.forename: Dudley K
authors.initials: DK
authors.lastname: Strickland
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004622:Embryo, Mammalian; D004705:Endocytosis / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D051379:Mice; D008970:Molecular Weight; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D020539:Sequence Analysis, Protein; D014162:Transfection / Q000379:methods
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C561588:LDLRAD3 protein, human; D012333:RNA, Messenger; D011973:Receptors, LDL