title: Decreased Levels of VAMP2 and Monomeric Alpha-Synuclein Correlate with Duration of Dementia.
abstract: Alpha-synuclein (α-syn) aggregations are the key pathological hallmark of dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), but are also frequently present in Alzheimer's disease (AD). Much remains unknown about the role of α-syn in the synapse and the wider role of synaptic dysfunction in these dementias. Changes in concentrations of key 'SNAP (Soluble N-ethylmaleimide Sensitive Factor Attachment Protein) Receptor' (SNARE) proteins as a consequence of alterations in the aggregation state of α-syn may contribute to synaptic dysfunction in patients with DLB, PDD, and AD and result in impaired cognition. We have studied a large cohort (n = 130) of autopsy confirmed DLB, PDD, AD, and control brains. Using semi-quantitative western blotting, we have demonstrated significant changes across the diagnostic groups of DLB, PDD, and AD in the SNARE and vesicle proteins syntaxin, Munc18, VAMP2, and monomeric α-syn in the prefrontal cortex, with a significant reduction of Munc18 in AD patients (p <  0.001). This correlated to the final MMSE score before death (p = 0.016). We also identified a significant negative correlation between the duration of dementia and the levels of the binding partners VAMP2 (p = 0.0004) and monomeric α-syn (p = 0.0002). Our findings may indicate that an upregulation of SNARE complex related proteins occurs in the early stages of disease as an attempt at compensating for failing synapses, prior to widespread deposition of pathological α-syn.
authors.affiliation: Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Vallortigara
authors.affiliation: Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Whitfield
authors.affiliation: Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: William
authors.initials: W
authors.lastname: Quelch
authors.affiliation: Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Amani
authors.initials: A
authors.lastname: Alghamdi
authors.affiliation: Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Howlett
authors.affiliation: Division of Neuropathology, Institute of Pathology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Hortobágyi
authors.affiliation: Institute of Neuroscience, Newcastle University, CAV, Newcastle upon Tyne, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: Johnson
authors.affiliation: Institute of Neuroscience, Newcastle University, CAV, Newcastle upon Tyne, UK.
authors.forename: Johannes
authors.initials: J
authors.lastname: Attems
authors.affiliation: Institute of Neuroscience, Newcastle University, CAV, Newcastle upon Tyne, UK.|Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors.forename: John T
authors.initials: JT
authors.lastname: O'Brien
authors.affiliation: Institute of Neuroscience, Newcastle University, CAV, Newcastle upon Tyne, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Clive G
authors.initials: CG
authors.lastname: Ballard
authors.affiliation: Department of Neurobiology, Ward Sciences and Society, Karolinska Institute, Stockholm, Sweden.|Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
authors.forename: Dag
authors.initials: D
authors.lastname: Aarsland
authors.affiliation: Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Francis
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000704:Analysis of Variance; D003072:Cognition Disorders / Q000209:etiology; D003704:Dementia / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008609:Mental Status Schedule; D009483:Neuropsychological Tests; D012044:Regression Analysis; D016708:Synaptophysin / Q000378:metabolism; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016708:Synaptophysin; C494807:VAMP2 protein, human; D050988:Vesicle-Associated Membrane Protein 2; D051844:alpha-Synuclein; D016875:tau Proteins
keywords: Alpha-synuclein; Alzheimer’s disease; Parkinson’s disease dementia; SNARE process; VAMP2; dementia with lewy bodies; munc18; synaptic dysfunction