Abstract
BackgroundThe Aβ peptide that accumulates in Alzheimer’s disease (AD) is derived from amyloid precursor protein (APP) following proteolysis by β- and γ-secretases. Substantial evidence indicates that alterations in APP trafficking within the secretory and endocytic pathways directly impact the interaction of APP with these secretases and subsequent Aβ production. Various members of the low-density lipoprotein receptor (LDLR) family have been reported to play a role in APP trafficking and processing and are important risk factors in AD. We recently characterized a distinct member of the LDLR family called LDLR-related protein 10 (LRP10) that shuttles between the trans-Golgi Network (TGN), plasma membrane (PM), and endosomes. Here we investigated whether LRP10 participates in APP intracellular trafficking and Aβ production.ResultsIn this report, we provide evidence that LRP10 is a functional APP receptor involved in APP trafficking and processing. LRP10 interacts directly with the ectodomain of APP and colocalizes with APP at the TGN. Increased expression of LRP10 in human neuroblastoma SH-SY5Y cells induces the accumulation of mature APP in the Golgi and reduces its presence at the cell surface and its processing into Aβ, while knockdown of LRP10 expression increases Aβ production. Mutations of key motifs responsible for the recycling of LRP10 to the TGN results in the aberrant redistribution of APP with LRP10 to early endosomes and a concomitant increase in APP β-cleavage into Aβ. Furthermore, expression of LRP10 is significantly lower in the post-mortem brain tissues of AD patients, supporting a possible role for LRP10 in AD.ConclusionsThe present study identified LRP10 as a novel APP sorting receptor that protects APP from amyloidogenic processing, suggesting that a decrease in LRP10 function may contribute to the pathogenesis of Alzheimer’s disease.
Highlights
Amyloid-β (Aβ) peptide accumulation in the brain is central to the pathogenesis of Alzheimer’s disease (AD)
low-density lipoprotein receptor (LDLR)-related protein 10 (LRP10) is a novel APPinteracting protein We initially evaluated the ability of LRP10 to bind amyloid precursor protein (APP) since such binding would indicate that LRP10 plays a role as an intracellular APP receptor
This interaction was confirmed using untagged APP (Additional file 1: Figure S1) and using a combination of lysates from cells that expressed LRP10-HA and green fluorescent protein (GFP)-APP separately (Additional file 2: Figure S2). These results indicated that overexpressed APP and LRP10-HA interact within cell lysates
Summary
Amyloid-β (Aβ) peptide accumulation in the brain is central to the pathogenesis of Alzheimer’s disease (AD). Aβ is produced by the serial proteolysis of amyloid precursor protein (APP) by secretases [1]. Non-amyloidogenic processing occurs mainly at the cell surface, where α-secretase and γ-secretase cleave APP into a soluble sAPPα fragment and non-toxic peptide p3. Amyloidogenic processing involves transit through endocytic organelles, where APP encounters β- and γ-secretases that cleave it into a soluble sAPPβ fragment and toxic Aβ peptides [2]. APP-interacting proteins that alter APP trafficking impact Aβ production. The Aβ peptide that accumulates in Alzheimer’s disease (AD) is derived from amyloid precursor protein (APP) following proteolysis by β- and γ-secretases. Substantial evidence indicates that alterations in APP trafficking within the secretory and endocytic pathways directly impact the interaction of APP with these secretases and subsequent Aβ production. We investigated whether LRP10 participates in APP intracellular trafficking and Aβ production
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
