Spatiotemporal sphingosine-1-phosphate receptor 3 expression within the cerebral vasculature after ischemic stroke.

Sphingosine-1-phosphate receptors (S1PRs) are promising therapeutic targets in cardiovascular disease, including ischemic stroke. However, important spatiotemporal information for alterations of S1PR expression is lacking. Here, we investigated the role of S1PR3 in ischemic stroke in rodent models and patient samples. We show that S1PR3 is acutely upregulated in perilesional reactive astrocytes after stroke, and that stroke volume and behavioral deficits are improved in mice lacking S1PR3. Further, we find that administration of an S1PR3 antagonist at 4-h post-stroke, but not at later timepoints, improves stroke outcome. Lastly, we observed higher plasma S1PR3 concentrations in experimental stroke and in patients with ischemic stroke. Together, our results establish S1PR3 as a potential drug target and biomarker in ischemic stroke.

Microvascular blood-brain barrier alterations in isolated brain capillaries of mice over-expressing alpha-synuclein (Thy1-aSyn line 61).

Dysfunction of the blood-brain barrier (BBB) is suggested to play a critical role in the pathological mechanisms of Parkinson's disease (PD). PD-related pathology such as alpha-synuclein accumulation and inflammatory processes potentially affect the integrity of the BBB early in disease progression, which in turn may alter the crosstalk of the central and peripheral immune response. Importantly, BBB dysfunction could also affect drug response in PD. Here we analyzed microvascular changes in isolated brain capillaries and brain sections on a cellular and molecular level during disease progression in an established PD mouse model that overexpresses human wild-type alpha-synuclein (Thy1-aSyn, line 61). BBB alterations observed in Thy1-aSyn mice included reduced vessel density, reduced aquaporin-4 coverage, reduced P-glycoprotein expression, increased low-density lipoprotein receptor-related protein 1 expression, increased pS129-alpha-synuclein deposition, and increased adhesion protein and matrix metalloprotease expression together with alterations in tight junction proteins. Striatal capillaries presented with more dysregulated BBB integrity markers compared to cortical capillaries. These alterations of BBB integrity lead, however, not to an overt IgG leakage in brain parenchyma. Our data reveals intricate alterations in key proteins of BBB function together with histological evidence for altered structure of the brain vasculature. Thy1-aSyn mice represent a useful model to investigate therapeutic targeting of BBB alterations in synucleinopathies.