title: The 37kDa/67kDa laminin receptor acts as a receptor for Aβ42 internalization.
abstract: Neuronal loss is a major neuropathological hallmark of Alzheimer's disease (AD). The associations between soluble Aβ oligomers and cellular components cause this neurotoxicity. The 37 kDa/67 kDa laminin receptor (LRP/LR) has recently been implicated in Aβ pathogenesis. In this study the mechanism underlying the pathological role of LRP/LR was elucidated. Försters Resonance Energy Transfer (FRET) revealed that LRP/LR and Aβ form a biologically relevant interaction. The ability of LRP/LR to form stable associations with endogenously shed Aβ was confirmed by pull down assays and Aβ-ELISAs. Antibody blockade of this association significantly lowered Aβ42 induced apoptosis. Furthermore, antibody blockade and shRNA mediated downregulation of LRP/LR significantly hampered Aβ42 internalization. These results suggest that LRP/LR is a receptor for Aβ42 internalization, mediating its endocytosis and contributing to the cytotoxicity of the neuropeptide by facilitating intra-cellular Aβ42 accumulation. These findings recommend anti-LRP/LR specific antibodies and shRNAs as potential therapeutic tools for AD treatment.
authors.affiliation: School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits 2050, Johannesburg, Republic of South Africa.
authors.forename: Bianca
authors.initials: B
authors.lastname: Da Costa Dias
authors.affiliation: School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits 2050, Johannesburg, Republic of South Africa.
authors.forename: Katarina
authors.initials: K
authors.lastname: Jovanovic
authors.affiliation: School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits 2050, Johannesburg, Republic of South Africa.
authors.forename: Danielle
authors.initials: D
authors.lastname: Gonsalves
authors.affiliation: School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits 2050, Johannesburg, Republic of South Africa.
authors.forename: Kiashanee
authors.initials: K
authors.lastname: Moodley
authors.affiliation: Affimed Therapeutics AG, Technologiepark, Im Neuenheimer Feld 582, 69120 Heidelberg, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Reusch
authors.affiliation: Affimed Therapeutics AG, Technologiepark, Im Neuenheimer Feld 582, 69120 Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knackmuss
authors.affiliation: Antiviral Gene Therapy Research Unit (AGTRU), Department of Molecular Medicine & Haematology, School of Pathology, University of the Witwatersrand, Private Bag 3, Wits 2050, Johannesburg, Republic of South Africa.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Weinberg
authors.affiliation: Affimed Therapeutics AG, Technologiepark, Im Neuenheimer Feld 582, 69120 Heidelberg, Germany.
authors.forename: Melvyn
authors.initials: M
authors.lastname: Little
authors.affiliation: School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits 2050, Johannesburg, Republic of South Africa.
authors.forename: Stefan F T
authors.initials: SF
authors.lastname: Weiss
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D017209:Apoptosis; D004705:Endocytosis; D057809:HEK293 Cells; D006801:Humans; D010446:Peptide Fragments / Q000378:metabolism*; D011485:Protein Binding; D055550:Protein Stability; D021381:Protein Transport; D017474:Receptors, Laminin / Q000378:metabolism; D012269:Ribosomal Proteins
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C510624:RPSA protein, human; D017474:Receptors, Laminin; D012269:Ribosomal Proteins; C075222:amyloid beta-protein (1-42)