Journal
NEUROCHEMISTRY INTERNATIONAL
Volume 80, Issue -, Pages 87-98Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuint.2014.12.002
Keywords
Vascular dementia; Synaptic failure; Clathrin; Deamidation; Synapsin 1; alpha/beta-tubulins
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Funding
- Singapore National Research Foundation under CBRG grant [NMRC/CBRG/0004/2012]
- Singapore Ministry of Education [Tier1 : RGT15/13]
- Newcastle Centre for Brain Ageing and Vitality (BBSRC)
- Newcastle Centre for Brain Ageing and Vitality (EPSRC)
- Newcastle Centre for Brain Ageing and Vitality (ESRC)
- Newcastle Centre for Brain Ageing and Vitality (MRC)
- UK Medical Research Council (MRC) [G0500247]
- Alzheimer's Research UK (UK)
- UK MRC [G0400074]
- Newcastle NIHR Biomedical Research Centre in Ageing and Age Related Diseases award
- Alzheimer's Society and Alzheimer's Research UK (ARUK), Brains for Dementia Research Project
- Newcastle Centre for Brain Ageing and Vitality (LLHW)
- MRC [G0500247, G0900652, G0502157, G0400074] Funding Source: UKRI
- Medical Research Council [G0502157, G0400074, G0500247, G0900652] Funding Source: researchfish
- The Dunhill Medical Trust [R277/0213] Funding Source: researchfish
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Progressive synaptic failure precedes the loss of neurons and decline in cognitive function in neurodegenerative disorders, but the specific proteins and posttranslational modifications that promote synaptic failure in vascular dementia (VaD) remain largely unknown. We therefore used an isobaric tag for relative and absolute proteomic quantitation (iTRAQ) to profile the synapse-associated proteome of post-mortem human cortex from vascular dementia patients and age-matched controls. Brain tissue from VaD patients exhibited significant down-regulation of critical synaptic proteins including clathrin (0.29; p < 1.0 center dot 10(-3)) and GDI1 (0.51; p = 3.0 center dot 10(-3)), whereas SNAP25 (1.6; p = 5.5 center dot 10(-3)), bassoon (1.4; p = 1.3 center dot 10(-3)), excitatory amino acid transporter 2(2.6: p = 9.2 center dot 10(-3)) and Ca2+/calmodulin dependent kinase II (1.6: p = 3.0 center dot 10(-2)) were substantially up-regulated. Our analyses further revealed divergent patterns of protein modification in the dementia patient samples, including a specific deamidation of synapsin1 predicted to compromise protein structure. Our results reveal potential molecular targets for intervention in synaptic failure and prevention of cognitive decline in VaD. (C) 2014 Elsevier Ltd. All rights reserved.
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