title: SEPT8 modulates β-amyloidogenic processing of APP by affecting the sorting and accumulation of BACE1.
abstract: Dysfunction and loss of synapses are early pathogenic events in Alzheimer's disease. A central step in the generation of toxic amyloid-β (Aβ) peptides is the cleavage of amyloid precursor protein (APP) by β-site APP-cleaving enzyme (BACE1). Here, we have elucidated whether downregulation of septin (SEPT) protein family members, which are implicated in synaptic plasticity and vesicular trafficking, affects APP processing and Aβ generation. SEPT8 was found to reduce soluble APPβ and Aβ levels in neuronal cells through a post-translational mechanism leading to decreased levels of BACE1 protein. In the human temporal cortex, we identified alterations in the expression of specific SEPT8 transcript variants in a manner that correlated with Alzheimer's-disease-related neurofibrillary pathology. These changes were associated with altered β-secretase activity. We also discovered that the overexpression of a specific Alzheimer's-disease-associated SEPT8 transcript variant increased the levels of BACE1 and Aβ peptides in neuronal cells. These changes were related to an increased half-life of BACE1 and the localization of BACE1 in recycling endosomes. These data suggest that SEPT8 modulates β-amyloidogenic processing of APP through a mechanism affecting the intracellular sorting and accumulation of BACE1.
authors.affiliation: Institute of Biomedicine, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland.
authors.forename: Kaisa M A
authors.initials: KM
authors.lastname: Kurkinen
authors.affiliation: Institute of Biomedicine, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland.
authors.forename: Mikael
authors.initials: M
authors.lastname: Marttinen
authors.affiliation: Eisai Ltd., Bernard Katz Building, University College London, London WC1E 6BT, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Turner
authors.affiliation: Institute of Biomedicine, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland.
authors.forename: Teemu
authors.initials: T
authors.lastname: Natunen
authors.affiliation: Institute of Biomedicine, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland.
authors.forename: Petra
authors.initials: P
authors.lastname: Mäkinen
authors.affiliation: Institute of Clinical Medicine - Neurology, School of Medicine, University of Eastern Finland and Department of Neurology, Kuopio University Hospital, 70211 Kuopio, Finland.
authors.forename: Fanni
authors.initials: F
authors.lastname: Haapalinna
authors.affiliation: Institute of Biomedicine, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Sarajärvi
authors.affiliation: Institute of Biomedicine, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland.
authors.forename: Sami
authors.initials: S
authors.lastname: Gabbouj
authors.affiliation: Institute of Clinical Medicine - Neurosurgery, School of Medicine, University of Eastern Finland and Neurosurgery of NeuroCenter, Kuopio University Hospital, 70211 Kuopio, Finland.
authors.forename: Mitja
authors.initials: M
authors.lastname: Kurki
authors.affiliation: Institute of Clinical Medicine - Neurosurgery, School of Medicine, University of Eastern Finland and Neurosurgery of NeuroCenter, Kuopio University Hospital, 70211 Kuopio, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Paananen
authors.affiliation: Institute of Clinical Medicine - Neurology, School of Medicine, University of Eastern Finland and Department of Neurology, Kuopio University Hospital, 70211 Kuopio, Finland.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Koivisto
authors.affiliation: Institute of Clinical Medicine - Pathology, School of Medicine, University of Eastern Finland and Department of Pathology, Kuopio University Hospital, 70211 Kuopio, Finland.
authors.forename: Tuomas
authors.initials: T
authors.lastname: Rauramaa
authors.affiliation: Institute of Clinical Medicine - Neurosurgery, School of Medicine, University of Eastern Finland and Neurosurgery of NeuroCenter, Kuopio University Hospital, 70211 Kuopio, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Leinonen
authors.affiliation: Department of Neurobiology, A.I. Virtanen, Institute for Molecular Sciences, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Tanila
authors.affiliation: Institute of Clinical Medicine - Neurology, School of Medicine, University of Eastern Finland and Department of Neurology, Kuopio University Hospital, 70211 Kuopio, Finland.
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.affiliation: Eisai Ltd., Bernard Katz Building, University College London, London WC1E 6BT, UK.
authors.forename: Fiona R
authors.initials: FR
authors.lastname: Lucas
authors.affiliation: Institute of Clinical Medicine - Neurology, School of Medicine, University of Eastern Finland and Department of Neurology, Kuopio University Hospital, 70211 Kuopio, Finland Department of Neurobiology, A.I. Virtanen, Institute for Molecular Sciences, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland annakaisa.haapasalo@uef.fi mikko.hiltunen@uef.fi.
authors.forename: Annakaisa
authors.initials: A
authors.lastname: Haapasalo
authors.affiliation: Institute of Biomedicine, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland Institute of Clinical Medicine - Neurology, School of Medicine, University of Eastern Finland and Department of Neurology, Kuopio University Hospital, 70211 Kuopio, Finland annakaisa.haapasalo@uef.fi mikko.hiltunen@uef.fi.
authors.forename: Mikko
authors.identifier: 0000-0003-3566-4096
authors.initials: M
authors.lastname: Hiltunen
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006207:Half-Life; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D021381:Protein Transport; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D058112:Septins / Q000235:genetics / Q000378:metabolism*; D013702:Temporal Lobe / Q000378:metabolism / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D012333:RNA, Messenger; C000621737:SEPT8 protein, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; C464445:SEPTIN8 protein, human; D058112:Septins
keywords: Alzheimer's disease; Amyloid precursor protein; Amyloid-β; BACE1; SEPT8