@article{65ca6e944a954a439974453f9ef3e586,
title = "Genetically-controlled Vesicle-Associated Membrane Protein 1 expression may contribute to Alzheimer's pathophysiology and susceptibility",
abstract = "Background: 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 A{\ss} release at the synapse and hence play an early role in Alzheimer's pathophysiology. Results: 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). Conclusions: Genetically regulated VAMP1 expression in the brain may modify both Alzheimer's disease risk and may contribute to Alzheimer's pathophysiology.",
keywords = "Alzheimer's disease, SNARE, Synapse, Vesicle-Associated Membrane Protein 1, β-amyloid",
author = "Daniel Sevlever and Fanggeng Zou and Li Ma and Sebastian Carrasquillo and Crump, {Michael G.} and Culley, {Oliver J.} and Hunter, {Talisha A.} and Bisceglio, {Gina D.} and Linda Younkin and Mariet Allen and Carrasquillo, {Minerva M.} and Sando, {Sigrid B.} and Aasly, {Jan O.} and Dickson, {Dennis W.} and Graff-Radford, {Neill R.} and Petersen, {Ronald C.} and Kevin Morgan and Olivia Belbin",
note = "Funding Information: We would like to thank Dr Steven G Younkin (Mayo Clinic, Jacksonville) for originally developing the idea and providing financial as well as critical support of the project. Olivia Belbin is funded by the Miguel Servet Associate Investigator Project Grant provided by FEDER (European Funds for Regional Development) and the Carlos III Institute of Health (Ministry for Economy and Competitivity, Spain). We thank contributors, including the Alzheimer disease centers that collected samples used in this study, as well as subjects and their families, whose help and participation made this work possible. We would like to thank the following members of the ARUK consortium for provision of DNA samples: Peter Passmore, David Craig, Janet Johnston, Bernadette McGuinness, Stephen Todd (Queen{\textquoteright}s University Belfast, UK), Reinhard Heun (Royal Derby Hospital, UK), Heike K{\"o}lsch (University of Bonn, Germany), Patrick G. Kehoe (University of Bristol, UK), Emma R.L.C. Vardy (Newcastle University, UK), David M. Mann, Julie Snowden, David Neary, Jenny Harris ,Stuart Pickering-Brown, Nigel M. Hooper (University of Manchester, UK), Christopher Medway, James Lowe, Kevin Morgan (University of Nottingham, UK), A. David Smith, Gordon Wilcock, Donald Warden (University of Oxford (OPTIMA), UK), Clive Holmes (University of Southampton, UK). Transgenic (VAMP1 +/-) mice were kindly provided by Ferenc Deak (University of Oklahoma). This work was supported by the National Institute on Aging (R01 AG018023 to NRG-R and SGY); Mayo Alzheimer{\textquoteright}s Disease Research Center (P50 AG016574 to RP, DWD, NRG-R, SGY); Mayo Alzheimer{\textquoteright}s Disease Patient Registry (U01AG006576 to RP); the National Institute on Aging (AG025711, AG017216, AG003949 to DWD); the Robert and Clarice Smith and Abigail Van Buren Alzheimer{\textquoteright}s Disease Research Program (to RP, DWD, NRG-R, and SGY) and the Palumbo Professorship in Alzheimer{\textquoteright}s Disease Research (to SGY). Samples from the National Cell Repository for Alzheimer{\textquoteright}s Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. Alzheimer{\textquoteright}s Research United Kingdom (ARUK) supported sample collections at the Universities of Nottingham, Manchester and Belfast. The Belfast group acknowledges support from the Alzheimer{\textquoteright}s Society, Ulster Garden Villages, N.Ireland Research & Development Office and the Royal College of Physicians/ Dunhill Medical Trust. The South West Dementia Brain Bank acknowledges support from Bristol Research into Alzheimer{\textquoteright}s and Care of the Elderly. The Charles Wolfson Charitable Trust supported the OPTIMA group. The Bonn group was supported by the German Federal Ministry of Education and Research Competence Network Dementia and Competence Network Degenerative Dementia, and by the Alfried Krupp von Bohlen und HalbachStiftung. Publisher Copyright: {\textcopyright} 2015 Sevlever et al.; licensee BioMed Central.",
year = "2015",
month = apr,
day = "9",
doi = "10.1186/s13024-015-0015-x",
language = "English (US)",
volume = "10",
journal = "Molecular Neurodegeneration",
issn = "1750-1326",
publisher = "BioMed Central",
number = "1",
}