Genetically-controlled Vesicle-Associated Membrane Protein 1 expression may contribute to Alzheimer's pathophysiology and susceptibility

Daniel Sevlever, Fanggeng Zou, Li Ma, Sebastian Carrasquillo, Michael G. Crump, Oliver J. Culley, Talisha A. Hunter, Gina D. Bisceglio, Linda Younkin, Mariet Allen, Minerva M Carrasquillo, Sigrid B. Sando, Jan O. Aasly, Dennis W Dickson, Neill R Graff Radford, Ronald Carl Petersen, Kevin Morgan, Olivia Belbin

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number18
JournalMolecular Neurodegeneration
Volume10
Issue number1
DOIs
StatePublished - Apr 9 2015

Fingerprint

Vesicle-Associated Membrane Protein 1
Alzheimer Disease
SNARE Proteins
Memory Disorders
Exocytosis
Presynaptic Terminals
Brain
Luciferases
Reporter Genes
Amyloid
Neurodegenerative Diseases
Synapses
Case-Control Studies
Homeostasis
Cell Death

Keywords

  • Alzheimer's disease
  • SNARE
  • Synapse
  • Vesicle-Associated Membrane Protein 1
  • β-amyloid

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Clinical Neurology
  • Molecular Biology

Cite this

Genetically-controlled Vesicle-Associated Membrane Protein 1 expression may contribute to Alzheimer's pathophysiology and susceptibility. / Sevlever, Daniel; Zou, Fanggeng; Ma, Li; Carrasquillo, Sebastian; Crump, Michael G.; Culley, Oliver J.; Hunter, Talisha A.; Bisceglio, Gina D.; Younkin, Linda; Allen, Mariet; Carrasquillo, Minerva M; Sando, Sigrid B.; Aasly, Jan O.; Dickson, Dennis W; Graff Radford, Neill R; Petersen, Ronald Carl; Morgan, Kevin; Belbin, Olivia.

In: Molecular Neurodegeneration, Vol. 10, No. 1, 18, 09.04.2015.

Research output: Contribution to journalArticle

Sevlever, D, Zou, F, Ma, L, Carrasquillo, S, Crump, MG, Culley, OJ, Hunter, TA, Bisceglio, GD, Younkin, L, Allen, M, Carrasquillo, MM, Sando, SB, Aasly, JO, Dickson, DW, Graff Radford, NR, Petersen, RC, Morgan, K & Belbin, O 2015, 'Genetically-controlled Vesicle-Associated Membrane Protein 1 expression may contribute to Alzheimer's pathophysiology and susceptibility', Molecular Neurodegeneration, vol. 10, no. 1, 18. https://doi.org/10.1186/s13024-015-0015-x
Sevlever, Daniel ; Zou, Fanggeng ; Ma, Li ; Carrasquillo, Sebastian ; Crump, Michael G. ; Culley, Oliver J. ; Hunter, Talisha A. ; Bisceglio, Gina D. ; Younkin, Linda ; Allen, Mariet ; Carrasquillo, Minerva M ; Sando, Sigrid B. ; Aasly, Jan O. ; Dickson, Dennis W ; Graff Radford, Neill R ; Petersen, Ronald Carl ; Morgan, Kevin ; Belbin, Olivia. / Genetically-controlled Vesicle-Associated Membrane Protein 1 expression may contribute to Alzheimer's pathophysiology and susceptibility. In: Molecular Neurodegeneration. 2015 ; Vol. 10, No. 1.
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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.",
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AU - Sevlever, Daniel

AU - Zou, Fanggeng

AU - Ma, Li

AU - Carrasquillo, Sebastian

AU - Crump, Michael G.

AU - Culley, Oliver J.

AU - Hunter, Talisha A.

AU - Bisceglio, Gina D.

AU - Younkin, Linda

AU - Allen, Mariet

AU - Carrasquillo, Minerva M

AU - Sando, Sigrid B.

AU - Aasly, Jan O.

AU - Dickson, Dennis W

AU - Graff Radford, Neill R

AU - Petersen, Ronald Carl

AU - Morgan, Kevin

AU - Belbin, Olivia

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N2 - 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.

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