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 Aß 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.
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Fl, 32224, USA. Sevlever.Daniel@Mayo.edu.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sevlever
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Fl, 32224, USA. Fanggeng.Zou@cchmc.org.|Human Genetics Division, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, 45229, USA. Fanggeng.Zou@cchmc.org.
authors.forename: Fanggeng
authors.initials: F
authors.lastname: Zou
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Fl, 32224, USA. ma.li@mayo.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Fl, 32224, USA. seb88c@gmail.com.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Carrasquillo
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Fl, 32224, USA. mgcrump@ucdavis.edu.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Crump
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Fl, 32224, USA. oliver.culley@hotmail.co.uk.
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Culley
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Fl, 32224, USA. tahunter82@gmail.com.
authors.forename: Talisha A
authors.initials: TA
authors.lastname: Hunter
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Fl, 32224, USA. bisceglio.gina@mayo.edu.
authors.forename: Gina D
authors.initials: GD
authors.lastname: Bisceglio
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Fl, 32224, USA. lhyounkin1@gmail.com.
authors.forename: Linda
authors.initials: L
authors.lastname: Younkin
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Fl, 32224, USA. Allen.Mariet@mayo.edu.
authors.forename: Mariet
authors.initials: M
authors.lastname: Allen
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Fl, 32224, USA. Carrasquillo.Minerva@mayo.edu.
authors.forename: Minerva M
authors.initials: MM
authors.lastname: Carrasquillo
authors.affiliation: Department of Neurology, St. Olav's Hospital, Edvard Griegs Gate 8, 7006, Trondheim, Norway. sigrid.b.sando@ntnu.no.|Department of Neuroscience, Norwegian University of Science and Technology, NTNU, 7491, Trondheim, Norway. sigrid.b.sando@ntnu.no.
authors.forename: Sigrid B
authors.initials: SB
authors.lastname: Sando
authors.affiliation: Department of Neuroscience, Norwegian University of Science and Technology, NTNU, 7491, Trondheim, Norway. jan.aasly@ntnu.no.
authors.forename: Jan O
authors.initials: JO
authors.lastname: Aasly
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Fl, 32224, USA. Dickson.dennis@mayo.edu.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Neurology, Mayo Clinic College of Medicine, Jacksonville, Fl, 32224, USA. graff-radford.neill@mayo.edu.
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.affiliation: Department of Neurology and the Mayo Alzheimer Disease Research Center, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. Petersen.ronald@mayo.edu.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Ferenc
authors.initials: F
authors.lastname: Deák
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Fl, 32224, USA. obelbin@santpau.cat.|Memory Disorders Unit, Institute of Biomedical Investigation Sant Pau (IIB Sant Pau), Autonomous University of Barcelona (UAB), Barcelona, Spain. obelbin@santpau.cat.
authors.forename: Olivia
authors.initials: O
authors.lastname: Belbin
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D051379:Mice; D013569:Synapses / Q000378:metabolism; D050987:Vesicle-Associated Membrane Protein 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D050987:Vesicle-Associated Membrane Protein 1