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Cited by 77Alzheimer's disease research and treatmentsCellular transport and secretionNeuroinflammation and Neurodegeneration Mechanisms

LDLR-related protein 10 (LRP10) regulates amyloid precursor protein (APP) trafficking and processing: evidence for a role in Alzheimer’s disease

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Brodeur, Julie, Thériault, Caroline, Lessard-Beaudoin, Mélissa, Marcil, Alexandre, Dahan, Sophie, Lavoie, Christine·2012·Molecular Neurodegeneration
DOI 10.1186/1750-1326-7-31PMC PMC3520120
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Abstract

Background: 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. 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. Results: In 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. Conclusions: The 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.

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  • Over-expression of LRP10 in human neuroblastoma SH-Sy5y cells led to accelerated APP transport from TGN to the plasma membrane with increased APP maturation and reduced Aβ production.

    “Over-expression of LRP10 in human neuroblastoma SH-Sy5y cells led to an accelerated APP transport from TGN to the plasma membrane with increased APP maturation and reduced Aβ production [48].”

    From Sex specific molecular networks and key drivers of Alzheimer’s disease (2023) · cites this paper as [48]

    The Results report that LRP10 overexpression in SH-SY5Y cells increased the amount of mature APP and reduced Aβ40 production. But they report APP accumulation in the TGN and less APP at the cell surface, suggesting retention rather than accelerated transport to the plasma membrane. Pulse-chase experiments also found similar maturation kinetics, so the increased mature APP does not establish faster maturation. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • In female APOE4+/- AD brains, reduction in LRP10 protein expression may result in increased Aβ production with impaired APP trafficking as well as reduced Aβ clearance by microglia, leading to AD pathological changes.

    “It is possible that in female APOE4+/- AD brains, reduction in LRP10 protein expression may result in an increased Aβ production with impaired APP trafficking [48] as well as a reduced Aβ clearance by microglia (as supported by our data) leading to AD pathological changes.”

    From Sex specific molecular networks and key drivers of Alzheimer’s disease (2023) · cites this paper as [48]

  • LRP10 was previously implicated in APP trafficking and processing, with subcellular localization in the trans-Golgi network (TGN), plasma membrane and endosomes.

    “LRP10 was previously implicated in APP trafficking and processing [48] with a subcellular localization in the trans-Golgi network (TGN), plasma membrane and endosomes.”

    From Sex specific molecular networks and key drivers of Alzheimer’s disease (2023) · cites this paper as [48]

  • LRP10 protein levels were previously shown to be significantly lower in the frontal cortex and hippocampus of AD brains than in controls, with a greater extent of reduction in female AD subjects than in male counterparts.

    “The LRP10 protein levels were previously shown to be significantly lower in the frontal cortex and hippocampus of AD brains than those in controls with a greater extent of reduction in female AD subjects than in male counterparts [48].”

    From Sex specific molecular networks and key drivers of Alzheimer’s disease (2023) · cites this paper as [48]

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Authors
Brodeur, J., Thériault, C., Lessard-Beaudoin, M., Marcil, A., Dahan, S., & Lavoie, C.
Affiliations
  • Université de Sherbrooke (CA)
  • PerkinElmer Biosignal (CA)
Corresponding author
Lavoie, Christine
ORCID
Lavoie, Christine
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2012-06-26
Volume
7
Issue
1
Pages
31-31
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/1750-1326-7-31
PMC
PMC3520120
OpenAlex
W2129354516
Cited by
77
References
2
Citations by year
2026: 2 · 2025: 2 · 2024: 22 · 2023: 4 · 2022: 3 · 2021: 6 · 2020: 8 · 2019: 7 · 2018: 4 · 2017: 5 · 2016: 3 · 2015: 3 · 2014: 8
FWCI
2.36
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Alzheimer Society
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
amyloid precursor protein, APP trafficking, amyloid-beta production, trans-Golgi network, endosomes, Alzheimer's disease
MeSH terms
Alzheimer Disease, Animals, Cell Membrane, Cells, Cultured, Golgi Apparatus, Humans, Protein Processing, Post-Translational, Endosomes, Amyloid beta-Protein Precursor, Protein Transport, trans-Golgi Network, LDL-Receptor Related Proteins, Mice, Amyloid Precursor Protein Secretases

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