title: High resolution imaging study of interactions between the 37 kDa/67 kDa laminin receptor and APP, beta-secretase and gamma-secretase in Alzheimer's disease.
abstract: Alzheimer's disease (AD) is the most prevalent form of dementia affecting the elderly. Neurodegeneration is caused by the amyloid beta (Aβ) peptide which is generated from the sequential proteolytic cleavage of the Amyloid Precursor Protein (APP) by the β- and γ- secretases. Previous reports revealed that the 37 kDa/67 kDa laminin receptor (LRP/LR) is involved in APP processing, however, the exact mechanism by which this occurs remains largely unclear. This study sought to assess whether LRP/LR interacted with APP, β- or γ-secretase. Detailed confocal microscopy revealed that LRP/LR showed a strong co-localisation with APP, β- and γ-secretase, respectively, at various sub-cellular locations. Superresolution Structured Illumination Microscopy (SR-SIM) showed that interactions were unlikely between LRP/LR and APP and β-secretase, respectively, while there was strong co-localisation between LRP/LR and γ-secretase at this 80 nm resolution. FRET was further employed to assess the possibility of protein-protein interactions and only an interaction between LRP/LR and γ-secretase was found. FLAG co-immunoprecipitation confirmed these findings as LRP/LR co-immunoprecipitated with γ-secretase, but failed to do so with APP. These findings indicate that LRP/LR exerts its influence on Aβ shedding via a direct interaction with the γ-secretase and possibly an indirect interaction with the β-secretase.
authors: School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, Republic of South Africa.
authors: Katarina
authors: K
authors: Jovanovic
authors: Department of Physiological Sciences, University of Stellenbosch, Stellenbosch, Republic of South Africa.
authors: Ben
authors: B
authors: Loos
authors: School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, Republic of South Africa.
authors: Bianca
authors: B
authors: Da Costa Dias
authors: Department of Internal Medicine, University of the Witwatersrand, Johannesburg, Republic of South Africa.
authors: Clement
authors: C
authors: Penny
authors: School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, Republic of South Africa.
authors: Stefan F T
authors: SF
authors: Weiss
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D002460:Cell Line; D017930:Genes, Reporter; D006801:Humans; D057054:Molecular Imaging / Q000379:methods; D011485:Protein Binding; D021381:Protein Transport; D017474:Receptors, Laminin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D017474:Receptors, Laminin; D053829:Amyloid Precursor Protein Secretases