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

Article type: Research Article

Authors: Vallortigara, Julie^a | Whitfield, David^{a; *} | Quelch, William^a | Alghamdi, Amani^a | Howlett, David^a | Hortobágyi, Tibor^b | Johnson, Mary^c | Attems, Johannes^c | O’Brien, John T.^{c; d} | Thomas, Alan^c | Ballard, Clive G.^a | Aarsland, Dag^{e; f} | Francis, Paul T.^a

Affiliations: [a] Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK | [b] Division of Neuropathology, Institute of Pathology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary | [c] Institute of Neuroscience, Newcastle University, CAV, Newcastle upon Tyne, UK | [d] Department of Psychiatry, University of Cambridge, Cambridge, UK | [e] Department of Neurobiology, Ward Sciences and Society, Karolinska Institute, Stockholm, Sweden | [f] Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway

Correspondence: [*] Correspondence to: Dr. David Whitfield, Wolfson Centre for Age Related Diseases, King’s College London, SE1 1UL, UK. Tel.: +44 02078486910; E-mail: david.r.whitfield@kcl.ac.uk.

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.

Keywords: Alpha-synuclein, Alzheimer’s disease, dementia with lewy bodies, munc18, Parkinson’s disease dementia, SNARE process, synaptic dysfunction, VAMP2

DOI: 10.3233/JAD-150707

Journal: Journal of Alzheimer's Disease, vol. 50, no. 1, pp. 101-110, 2016