Genetically-controlled Vesicle-Associated Membrane Protein 1 expression may contribute to Alzheimer's pathophysiology and susceptibility
Sevlever, Daniel (Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville)
Zou, Fanggeng (Cincinnati Children's Hospital Medical Center)
Ma, Li (Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville)
Carrasquillo, Sebastian (Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville)
Crump, Michael G. (Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville)
Culley, Oliver J. (Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville)
Hunter, Talisha A. (Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville)
Bisceglio, Gina D. (Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville)
Younkin, Linda (Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville)
Allen, Mariet (Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville)
Carrasquillo, Minerva M. (Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville)
Sando, Sigrid B. (Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway)
Aasly, Jan O. (Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway)
Dickson, Dennis W. (Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville)
Graff-Radford, Neill R. (Department of Neurology, Mayo Clinic College of Medicine, Jacksonville)
Petersen, Ronald C. (Department of Neurology and the Mayo Alzheimer Disease Research Center, Mayo Clinic College of Medicine, Rochester, Minnesota)
Belbin, Olivia (Institut d'Investigació Biomèdica Sant Pau)
Institut d'Investigació Biomèdica Sant Pau

Data:	2015
Resum:	Ajuts: Programa Miguel Servet de l'Instituto de Salud Carlos III i FEDER (European Funds for Regional Development).
Resum:	Alzheimer's disease is a neurodegenerative disorder in which extracellular deposition of β-amyloid (Aβ) oligomers causes synaptic injury resulting in early memory loss, altered homeostasis, accumulation of hyperphosphorylated tau and cell death. Since proteins in the SNAP (Soluble N-ethylmaleimide-sensitive factor Attachment Protein) REceptors (SNARE) complex are essential for neuronal Aβ release at pre-synaptic terminals, we hypothesized that genetically controlled SNARE expression could alter neuronal Aß release at the synapse and hence play an early role in Alzheimer's pathophysiology. Here we report 5 polymorphisms in Vesicle-Associated Membrane Protein 1 (VAMP1), a gene encoding a member of the SNARE complex, associated with bidirectionally altered cerebellar VAMP1 transcript levels (all p < 0. 05). At the functional level, we demonstrated that control of VAMP1 expression by heterogeneous knockdown in mice resulted in up to 74% reduction in neuronal Aβ exocytosis (p < 0. 001). We performed a case-control association study of the 5 VAMP1 expression regulating polymorphisms in 4,667 Alzheimer's disease patients and 6,175 controls to determine their contribution to Alzheimer's disease risk. We found that polymorphisms associated with increased brain VAMP1 transcript levels conferred higher risk for Alzheimer's disease than those associated with lower VAMP1 transcript levels (p = 0. 03). Moreover, we also report a modest protective association for a common VAMP1 polymorphism with Alzheimer's disease risk (OR = 0. 88, p = 0. 03). This polymorphism was associated with decreased VAMP1 transcript levels (p = 0. 02) and was functionally active in a dual luciferase reporter gene assay (p < 0. 01). Genetically regulated VAMP1 expression in the brain may modify both Alzheimer's disease risk and may contribute to Alzheimer's pathophysiology. The online version of this article (doi:10. 1186/s13024-015-0015-x) contains supplementary material, which is available to authorized users.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	SNARE ; Vesicle-Associated Membrane Protein 1 ; β-amyloid ; Alzheimer's disease ; Synapse
Publicat a:	Molecular neurodegeneration, Vol. 10 (april 2015) , ISSN 1750-1326

Erratum: https://ddd.uab.cat/record/254452
DOI: 10.1186/s13024-015-0015-x
PMID: 25881291

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