Preclinical and Clinical Evidence for the Involvement of Sphingosine 1-Phosphate Signaling in the Pathophysiology of Vascular Cognitive Impairment.

Sphingosine 1-phosphates (S1Ps) are bioactive lipids that mediate a diverse range of effects through the activation of cognate receptors, S1P1-S1P5. Scrutiny of S1P-regulated pathways over the past three decades has identified important and occasionally counteracting functions in the brain and cerebrovascular system. For example, while S1P1 and S1P3 mediate proinflammatory effects on glial cells and directly promote endothelial cell barrier integrity, S1P2 is anti-inflammatory but disrupts barrier integrity. Cumulatively, there is significant preclinical evidence implicating critical roles for this pathway in regulating processes that drive cerebrovascular disease and vascular dementia, both being part of the continuum of vascular cognitive impairment (VCI). This is supported by clinical studies that have identified correlations between alterations of S1P and cognitive deficits. We review studies which proposed and evaluated potential mechanisms by which such alterations contribute to pathological S1P signaling that leads to VCI-associated chronic neuroinflammation and neurodegeneration. Notably, S1P receptors have divergent but overlapping expression patterns and demonstrate complex interactions. Therefore, the net effect produced by S1P represents the cumulative contributions of S1P receptors acting additively, synergistically, or antagonistically on the neural, vascular, and immune cells of the brain. Ultimately, an optimized therapeutic strategy that targets S1P signaling will have to consider these complex interactions.

Novel pathophysiological markers are revealed by iTRAQ-based quantitative clinical proteomics approach in vascular dementia.

Vascular dementia (VaD) is a leading cause of dementia in the elderly together with Alzheimer's disease with limited treatment options. Poor understanding of the pathophysiology underlying VaD is hindering the development of new therapies. Hence, to unravel its underlying molecular pathology, an iTRAQ-2D-LC-MS/MS strategy was used for quantitative analysis of pooled lysates from Brodmann area 21 of pathologically confirmed cases of VaD and matched non-neurological controls. A total of 144 differentially expressed proteins out of 2281 confidently identified proteins (false discovery rate=0.3%) were shortlisted for bioinformatics analysis. Western blot analysis of selected proteins using samples from individual patients (n=10 per group) showed statistically significant increases in the abundance of SOD1 and NCAM and reduced ATP5A in VaD. This suggested a state of hypometabolism and vascular insufficiency along with an inflammatory condition during VaD. Elevation of SOD1 and increasing trend for iron-storage proteins (FTL, FTH1) may be indicative of an oxidative imbalance that is accompanied by an aberrant iron metabolism. The synaptic proteins did not exhibit a generalized decrease in abundance (e.g. syntaxin) in the VaD subjects. This reported proteome offers a reference data set for future basic or translational studies on VaD. BIOLOGICAL SIGNIFICANCE: Our study is the first quantitative clinical proteomic study where iTRAQ-2D-LC-MS/MS strategy has been used to identify the differential proteome in the VaD cortex by comparing VaD and matched control subjects. We generate testable hypothesis about the involvement of various proteins in the vascular and parenchymal events during the evolution of VaD that finally leads to malfunction and demise of brain cells. This study also establishes quantitative proteomics as a complementary approach and viable alternative to existing neurochemical, electron microscopic and neuroimaging techniques that are traditionally being used to understand the molecular pathology of VaD. Our study could inspire fellow researchers to initiate similar retrospective studies targeting various ethnicities, age-groups or sub-types of VaD using brain samples available from brain banks across the world. Meta-analysis of these studies in the future may be able to shortlist candidate proteins or pathways for rationale exploration of therapeutic targets or biomarkers for VaD.