Tags

Type your tag names separated by a space and hit enter

Relationship between ubiquilin-1 and BACE1 in human Alzheimer's disease and APdE9 transgenic mouse brain and cell-based models.
Neurobiol Dis. 2016 Jan; 85:187-205.ND

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+Show Affiliations

Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.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.Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.Department of Medical Biochemistry and Genetics, Institute of Biomedicine, Turku, Finland.Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.Neurosurgery sIA Group, Kuopio University Hospital, Kuopio, Finland.Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.Department of Pathology, Kuopio University Hospital, Kuopio, Finland; Institute of Clinical Medicine - Pathology, University of Eastern Finland, Kuopio, Finland.Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland; Neurosurgery of NeuroCenter, University of Eastern Finland, Kuopio, Finland.Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland.The Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland.Genetics and Aging Research Unit, Massachusetts General Hospital, Charlestown, Boston, MA 02129, United States; Harvard Medical School, Boston, MA 02129, United States.Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.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.Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland. Electronic address: mikko.hiltunen@uef.fi.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26563932

Citation

Natunen, Teemu, et al. "Relationship Between Ubiquilin-1 and BACE1 in Human Alzheimer's Disease and APdE9 Transgenic Mouse Brain and Cell-based Models." Neurobiology of Disease, vol. 85, 2016, pp. 187-205.
Natunen T, Takalo M, Kemppainen S, et al. Relationship between ubiquilin-1 and BACE1 in human Alzheimer's disease and APdE9 transgenic mouse brain and cell-based models. Neurobiol Dis. 2016;85:187-205.
Natunen, T., Takalo, M., Kemppainen, S., Leskelä, S., Marttinen, M., Kurkinen, K. M. A., Pursiheimo, J. P., Sarajärvi, T., Viswanathan, J., Gabbouj, S., Solje, E., Tahvanainen, E., Pirttimäki, T., Kurki, M., Paananen, J., Rauramaa, T., Miettinen, P., Mäkinen, P., Leinonen, V., ... Hiltunen, M. (2016). Relationship between ubiquilin-1 and BACE1 in human Alzheimer's disease and APdE9 transgenic mouse brain and cell-based models. Neurobiology of Disease, 85, 187-205. https://doi.org/10.1016/j.nbd.2015.11.005
Natunen T, et al. Relationship Between Ubiquilin-1 and BACE1 in Human Alzheimer's Disease and APdE9 Transgenic Mouse Brain and Cell-based Models. Neurobiol Dis. 2016;85:187-205. PubMed PMID: 26563932.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Relationship between ubiquilin-1 and BACE1 in human Alzheimer's disease and APdE9 transgenic mouse brain and cell-based models. AU - Natunen,Teemu, AU - Takalo,Mari, AU - Kemppainen,Susanna, AU - Leskelä,Stina, AU - Marttinen,Mikael, AU - Kurkinen,Kaisa M A, AU - Pursiheimo,Juha-Pekka, AU - Sarajärvi,Timo, AU - Viswanathan,Jayashree, AU - Gabbouj,Sami, AU - Solje,Eino, AU - Tahvanainen,Eveliina, AU - Pirttimäki,Tiina, AU - Kurki,Mitja, AU - Paananen,Jussi, AU - Rauramaa,Tuomas, AU - Miettinen,Pasi, AU - Mäkinen,Petra, AU - Leinonen,Ville, AU - Soininen,Hilkka, AU - Airenne,Kari, AU - Tanzi,Rudolph E, AU - Tanila,Heikki, AU - Haapasalo,Annakaisa, AU - Hiltunen,Mikko, Y1 - 2015/11/10/ PY - 2015/01/26/received PY - 2015/09/13/revised PY - 2015/11/07/accepted PY - 2015/11/14/entrez PY - 2015/11/14/pubmed PY - 2016/9/23/medline KW - APdE9 transgenic mice KW - Alzheimer's disease KW - Amyloid precursor protein (APP) KW - Amyloid-β (Aβ) KW - Beta-secretase 1 (BACE1) KW - Human brain KW - Lentivirus KW - Neuroinflammation KW - Tau SP - 187 EP - 205 JF - Neurobiology of disease JO - Neurobiol Dis VL - 85 N2 - 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. SN - 1095-953X UR - https://www.unboundmedicine.com/medline/citation/26563932/Relationship_between_ubiquilin_1_and_BACE1_in_human_Alzheimer's_disease_and_APdE9_transgenic_mouse_brain_and_cell_based_models_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(15)30084-X DB - PRIME DP - Unbound Medicine ER -