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

Julie Vallortigara, David Whitfield*, William Quelch, Amani Alghamdi, David Howlett, Tibor Hortobágyi, Mary Johnson, Johannes Attems, John T. O'Brien, Alan Thomas, Clive G. Ballard, Dag Aarsland, Paul T. Francis

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)101-110
Number of pages10
JournalJOURNAL OF ALZHEIMERS DISEASE
Volume50
Issue number1
DOIs
Publication statusPublished - 30 Nov 2015

Keywords

  • Alpha-synuclein
  • Alzheimer's disease
  • dementia with lewy bodies
  • munc18
  • Parkinson's disease dementia
  • SNARE process
  • synaptic dysfunction
  • VAMP2

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