Decreased Levels of VAMP2 and Monomeric Alpha-Synuclein Correlate with Duration of Dementia

TY - JOUR

T1 - Decreased Levels of VAMP2 and Monomeric Alpha-Synuclein Correlate with Duration of Dementia

AU - Vallortigara, Julie

AU - Whitfield, David

AU - Quelch, William

AU - Alghamdi, Amani

AU - Howlett, David

AU - Hortobágyi, Tibor

AU - Johnson, Mary

AU - Attems, Johannes

AU - O'Brien, John T.

AU - Thomas, Alan

AU - Ballard, Clive G.

AU - Aarsland, Dag

AU - Francis, Paul T.

PY - 2015/11/30

Y1 - 2015/11/30

N2 - Alpha-synuclein (β-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 β-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 β-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 β-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 β-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 β-syn.

AB - Alpha-synuclein (β-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 β-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 β-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 β-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 β-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 β-syn.

KW - Alpha-synuclein

KW - Alzheimer's disease

KW - dementia with lewy bodies

KW - munc18

KW - Parkinson's disease dementia

KW - SNARE process

KW - synaptic dysfunction

KW - VAMP2

UR - http://www.scopus.com/inward/record.url?scp=84954098113&partnerID=8YFLogxK

U2 - 10.3233/JAD-150707

DO - 10.3233/JAD-150707

M3 - Article

AN - SCOPUS:84954098113

SN - 1387-2877

VL - 50

SP - 101

EP - 110

JO - JOURNAL OF ALZHEIMERS DISEASE

JF - JOURNAL OF ALZHEIMERS DISEASE

IS - 1

ER -