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

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.

Molecular changes in the absence of severe pathology in the pulvinar in dementia with Lewy bodies

“…In contrast, we found the preservation of proteins necessary for vesicular exocytosis, such as SNAP25, STX1A, and SV2B . Despite the interaction of α‐synuclein with synaptic proteins, previous studies have not consistently demonstrated significantly lower levels of presynaptic markers in DLB …”

“…41 Despite the interaction of a-synuclein with synaptic proteins, previous studies have not consistently demonstrated significantly lower levels of presynaptic markers in DLB. 42 The role of glia in DLB has been a matter of controversy and debate, with conflicting reports in the literature. Microglial activation is induced by aggregated asynuclein in vitro, 43 although postmortem studies have reported inconsistent findings.…”

Increased phosphorylation of collapsin response mediator protein-2 at Thr514 correlates with β-amyloid burden and synaptic deficits in Lewy body dementias

“…However, pSer396 tau changes did not reach statistical significance due to variability (see Additional file 4: Figure S4a), and higher N ’s may be needed to have sufficient power to study potential correlations between different pCRMP2 species and tau phosphorylation, especially since certain pCRMP2, e.g., 3 F4 epitopes, are known to be associated with neurofibrillary tangles [55]. With regards to α-synuclein, we found no difference in levels of monomeric species in agreement with previous studies [48, 49], and no correlations between α-synuclein and pCRMP2 (Additional file 5: Figure S5). In contrast, α-synuclein phosphorylated at Ser129 in insoluble fractions was significantly elevated in DLB, whilst PDD showed intermediate levels, and may be more specific to [56], and pathogenic in [57], LBD, similar with previous finding [58] (Additional file 6: Figure S6).…”

“…2a). Interestingly, PDD and DLB are known to have similar α-synuclein loads as well as Lewy body burden [19, 48, 49] (also see Additional file 5: Figure S5), suggesting that at least some of the identified neurochemical differences between PDD and DLB could be driven by the different Aβ burden in the subtypes. This postulate is recently supported by the finding that low cerebrospinal fluid Aβ42 values predicted a more rapid cognitive decline in DLB [50].…”

A Lewy-testes demencia klinikai és neuropatológiai jellemzői

“…Szignifikáns csökkenés mutatkozik a szinaptikus vesiculák dokkolásában részt vevő synaptotagmin, synapsin, synaptophysin, VAMP2 és SNAP25 fehérjék szintjében [32]. Következésképpen a preszinaptikus neuronokból nem tudnak neurotranszmitterek felszabadulni, így a posztszinaptikus sejtek elvesztik "input"-jaikat, ami a központi idegrendszer kiterjedt funkciózavarához vezet, ezt a posztszinaptikus PSD95, valamint a neurogranin fehérje csökkent szintje is alátámasztani látszik.…”