Decreased Levels of VAMP2 and Monomeric Alpha-Synuclein Correlate with Duration of Dementia
O’Brien, John T
Ballard, Clive G
Francis, Paul T
VAMP2 correlates to duration of dementia
Journal of Alzheimer's Disease
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Vallortigara, J., Whitfield, D., Quelch, W., Alghamdi, A., Howlett, D., Hortobágyi, T., Johnson, M., et al. (2015). Decreased Levels of VAMP2 and Monomeric Alpha-Synuclein Correlate with Duration of Dementia. Journal of Alzheimer's Disease, 50 101-110. https://doi.org/10.3233/JAD-150707
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.
Alpha-synuclein, Alzheimer’s disease, dementia with lewy bodies, munc18, Parkinson’s disease dementia, SNARE process, synaptic dysfunction, VAMP2
The main funding was provided by the Alzheimer’s Society UK and the BUPA Foundation. The research in Newcastle was supported in part by the Dunhill Medical Trust (R173/1110). Tissue for this study was provided by (i) the Newcastle Brain Tissue Resource; (ii) the London Neurodegenerative Brain Bank; and (iii) the Thomas Willis Oxford Brain Collection. All three resources are funded in part by grants from the UK Medical Research Council and by Brains for Dementia Research, a joint venture between Alzheimer’s Society and Alzheimer’s Research UK. Professor Margaret Esiri and Drs. Olaf Ansorge, Safa Al-Sarraj, Istvan Bodi, and Andrew King are thanked for neuropathological diagnosis of cases. Dr. Claire Troakes at the MRC London Neurodegenerative Diseases Brain Bank is thanked for supplying tissue sections. The authors express their thanks to all the donors and brain banks for the tissue used in this study. This Newcastle Brain Tissue Resource is supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Unit based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University and the Medical Research Council and Brains for Dementia Research. The MRC London Neurodegenerative Diseases Brain Bank is funded by the Medical Research Council and Brains for Dementia Research. TH has received salary support from the Hungarian Brain Research Programme Grant No. KTIA_13_NAP-A-II/7. CB would like to thank the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and [Institute of psychiatry] King’s College London. This article presents independent research supported/funded by the National Institute for Health Research (NIHR). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
External DOI: https://doi.org/10.3233/JAD-150707
This record's URL: https://www.repository.cam.ac.uk/handle/1810/252858