title: Relationship between ubiquilin-1 and BACE1 in human Alzheimer's disease and APdE9 transgenic mouse brain and cell-based models.
abstract: Accumulation of β-amyloid (Aβ) and phosphorylated tau in the brain are central events underlying Alzheimer's disease (AD) pathogenesis. Aβ is generated from amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase-mediated cleavages. Ubiquilin-1, a ubiquitin-like protein, genetically associates with AD and affects APP trafficking, processing and degradation. Here, we have investigated ubiquilin-1 expression in human brain in relation to AD-related neurofibrillary pathology and the effects of ubiquilin-1 overexpression on BACE1, tau, neuroinflammation, and neuronal viability in vitro in co-cultures of mouse embryonic primary cortical neurons and microglial cells under acute neuroinflammation as well as neuronal cell lines, and in vivo in the brain of APdE9 transgenic mice at the early phase of the development of Aβ pathology. Ubiquilin-1 expression was decreased in human temporal cortex in relation to the early stages of AD-related neurofibrillary pathology (Braak stages 0-II vs. III-IV). There was a trend towards a positive correlation between ubiquilin-1 and BACE1 protein levels. Consistent with this, ubiquilin-1 overexpression in the neuron-microglia co-cultures with or without the induction of neuroinflammation resulted in a significant increase in endogenously expressed BACE1 levels. Sustained ubiquilin-1 overexpression in the brain of APdE9 mice resulted in a moderate, but insignificant increase in endogenous BACE1 levels and activity, coinciding with increased levels of soluble Aβ40 and Aβ42. BACE1 levels were also significantly increased in neuronal cells co-overexpressing ubiquilin-1 and BACE1. Ubiquilin-1 overexpression led to the stabilization of BACE1 protein levels, potentially through a mechanism involving decreased degradation in the lysosomal compartment. Ubiquilin-1 overexpression did not significantly affect the neuroinflammation response, but decreased neuronal viability in the neuron-microglia co-cultures under neuroinflammation. Taken together, these results suggest that ubiquilin-1 may mechanistically participate in AD molecular pathogenesis by affecting BACE1 and thereby APP processing and Aβ accumulation.
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Teemu
authors.initials: T
authors.lastname: Natunen
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland; Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Mari
authors.initials: M
authors.lastname: Takalo
authors.affiliation: Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Susanna
authors.initials: S
authors.lastname: Kemppainen
authors.affiliation: Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Stina
authors.initials: S
authors.lastname: Leskelä
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Mikael
authors.initials: M
authors.lastname: Marttinen
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Kaisa M A
authors.initials: KMA
authors.lastname: Kurkinen
authors.affiliation: Department of Medical Biochemistry and Genetics, Institute of Biomedicine, Turku, Finland.
authors.forename: Juha-Pekka
authors.initials: JP
authors.lastname: Pursiheimo
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Sarajärvi
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Jayashree
authors.initials: J
authors.lastname: Viswanathan
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Sami
authors.initials: S
authors.lastname: Gabbouj
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Eino
authors.initials: E
authors.lastname: Solje
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Eveliina
authors.initials: E
authors.lastname: Tahvanainen
authors.affiliation: Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Pirttimäki
authors.affiliation: Neurosurgery sIA Group, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Mitja
authors.initials: M
authors.lastname: Kurki
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Paananen
authors.affiliation: Department of Pathology, Kuopio University Hospital, Kuopio, Finland; Institute of Clinical Medicine - Pathology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Tuomas
authors.initials: T
authors.lastname: Rauramaa
authors.affiliation: Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Pasi
authors.initials: P
authors.lastname: Miettinen
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Petra
authors.initials: P
authors.lastname: Mäkinen
authors.affiliation: Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland; Neurosurgery of NeuroCenter, University of Eastern Finland, Kuopio, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Leinonen
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.affiliation: The Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Kari
authors.initials: K
authors.lastname: Airenne
authors.affiliation: Genetics and Aging Research Unit, Massachusetts General Hospital, Charlestown, Boston, MA 02129, United States; Harvard Medical School, Boston, MA 02129, United States.
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.affiliation: Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Tanila
authors.affiliation: Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland. Electronic address: annakaisa.haapasalo@uef.fi.
authors.forename: Annakaisa
authors.initials: A
authors.lastname: Haapasalo
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland. Electronic address: mikko.hiltunen@uef.fi.
authors.forename: Mikko
authors.initials: M
authors.lastname: Hiltunen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D000071183:Autophagy-Related Proteins; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D018920:Coculture Techniques; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: C545487:APP protein, human; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C054369:MAPT protein, human; D010446:Peptide Fragments; C107792:UBQLN1 protein, human; C538987:UBQLN1 protein, mouse; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse
keywords: APdE9 transgenic mice; Alzheimer's disease; Amyloid precursor protein (APP); Amyloid-β (Aβ); Beta-secretase 1 (BACE1); Human brain; Lentivirus; Neuroinflammation; Tau