title: Human brain proteins showing neuron-specific interactions with γ-secretase.
abstract: The transmembrane protease complex γ-secretase is a key enzyme in Alzheimer disease pathogenesis as it liberates the neurotoxic amyloid β-peptide (Aβ); however, the mechanism of regulation of its activity in various cell types and subcellular compartments is largely unknown. Several γ-secretase inhibitors have been developed, but none have been released due to side-effects that appear to arise from reduced processing of Notch, one of many γ-secretase substrates. Hence, it is desirable to specifically inhibit Aβ production. In our previous studies, we have identified several γ-secretase-associated proteins (GSAPs) from brain, which affect Aβ production without having any major effects on Notch processing. In the present study using detergent-resistant membranes prepared from brain, we have identified four GSAPs that affect Aβ production to a greater extent than Notch processing. We evaluated the interaction between GSAPs and γ-secretase in various cell types and their mRNA expression in various human organs. Using an in situ proximity ligation assay, we demonstrated that many GSAPs showed considerably greater interaction with γ-secretase in neurons than in human embryonic kidney cells stably over-expressing APP, and showed that several GSAPs are highly expressed in human brain. This study underscores the importance of studying protein-protein interactions in relevant cell types, and suggests that reducing Aβ production by interfering with brain- or neuron-specific γ-secretase/GSAP interactions may reduce the risk of unwanted side-effects associated with treatment of Alzheimer disease.
authors.affiliation: Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Huddinge, Sweden.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Huddinge, Sweden.
authors.forename: Ji-Yeun
authors.initials: JY
authors.lastname: Hur
authors.affiliation: Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Huddinge, Sweden.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kihara
authors.affiliation: Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Huddinge, Sweden.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Teranishi
authors.affiliation: Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Huddinge, Sweden.
authors.forename: Natsuko G
authors.initials: NG
authors.lastname: Yamamoto
authors.affiliation: Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Huddinge, Sweden.
authors.forename: Taizo
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Huddinge, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Wiehager
authors.affiliation: Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Huddinge, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Winblad
authors.affiliation: Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Huddinge, Sweden.
authors.forename: Lars O
authors.initials: LO
authors.lastname: Tjernberg
authors.affiliation: Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Huddinge, Sweden.
authors.forename: Sophia
authors.initials: S
authors.lastname: Schedin-Weiss
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D019922:GAP-43 Protein / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D051938:Munc18 Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D025941:Protein Interaction Mapping / Q000379:methods; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D051880:Receptors, Notch / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D019922:GAP-43 Protein; D008565:Membrane Proteins; D051938:Munc18 Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D051880:Receptors, Notch; C497937:STXBP1 protein, human; C106354:flotillins; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer disease; presenilin; protein interaction; proximity ligation assay; γ-secretase-associated protein