The proton-sensing receptors TDAG8 and GPR4 are differentially expressed in human and mouse oligodendrocytes: Exploring their role in neuroinflammation and multiple sclerosis.

Acidosis is one of the hallmarks of demyelinating central nervous system (CNS) lesions in multiple sclerosis (MS). The response to acidic pH is primarily mediated by a family of G protein-coupled proton-sensing receptors: OGR1, GPR4 and TDAG8. These receptors are inactive at alkaline pH, reaching maximal activation at acidic pH. Genome-wide association studies have identified a locus within the TDAG8 gene associated with several autoimmune diseases, including MS. Accordingly, we here found that expression of TDAG8, as opposed to GPR4 or OGR1, is upregulated in MS plaques. This led us to investigate the expression of TDAG8 in oligodendrocytes using mouse and human in vitro and in vivo models. We observed significant upregulation of TDAG8 in human MO3.13 oligodendrocytes during maturation and in response to acidic conditions. However, its deficiency did not impact normal myelination in the mouse CNS, and its expression remained unaltered under demyelinating conditions in mouse organotypic cerebellar slices. Notably, our data revealed no expression of TDAG8 in primary mouse oligodendrocyte progenitor cells (OPCs), in contrast to its expression in primary human OPCs. Our investigations have revealed substantial species differences in the expression of proton-sensing receptors in oligodendrocytes, highlighting the limitations of the employed experimental models in fully elucidating the role of TDAG8 in myelination and oligodendrocyte biology. Consequently, the study does not furnish robust evidence for the role of TDAG8 in such processes. Nonetheless, our findings tentatively point towards a potential association between TDAG8 and myelination processes in humans, hinting at a potential link between TDAG8 and the pathophysiology of MS and warrants further research.

New Remote Cerebral Microbleeds on T2*-Weighted Echo Planar MRI After Intravenous Thrombolysis for Acute Ischemic Stroke.

BACKGROUND: The main and well-defined complication of intravenous administration of recombinant tissue plasminogen activator (tPA) in patients with acute ischemic stroke (AIS) is symptomatic intracranial hemorrhage (sICH). However, rtPA might also be connected with the formation of cerebral microbleeds (CMBs), located remotely from the ischemic lesions, that may remain clinically silent. This association might be important because the load of CMBs has been associated with cognitive impairment. We investigated whether administration of rtPA in AIS results in the appearance of new CMBs and if the initial load of CMBs is associated with hemorrhagic transformation. METHODS: A total of fifty-nine consecutive patients with AIS treated with rtPA underwent MRI including T2*-weighted Echo Planar Imaging (T2*-EPI) shortly before and 7-9 days after rtPA administration. We calculated the load of new CMBs located outside the MR diffusion restriction area in the follow-up imaging and assessed hemorrhagic transformation with ECASS-II scoring. RESULTS: A total of forty-nine patients were included for the final analysis. On initial T2*-EPI-GRE, 37 baseline microbleeds (CMBs) were observed in 14 patients (28.6%). On follow-up T2*-EPI-GRE amount of CMBs increased to a total number of 103. New CMBs were found in 5 (14.3%) of 35 patients without and in 9 (64.3%) of 14 with any baseline CMBs. Multiple logistic regression analysis indicated that presence of baseline CMBs (risk ratio [RR] 5.95, 95% CI 2.69-13.20, p < 0.001) and lower platelets level (risk ratio [RR] 0.992, 95% CI 0.986-0.998, p = 0.007) were independently associated with new CMBs. The baseline load of CMBs was not associated with the risk of hemorrhagic transformation. CONCLUSION: In this study, new CMBs were found in nearly 30% of patients with AIS on the 7-9 days after rtPA treatment. Baseline CMBs correlated with a higher risk of new CMBs appearing after the rtPA treatment, independently of other factors. At the same time, in our sample, baseline CMBs did not correlate with an increased risk of hemorrhagic transformation. Since the associations between the CMBs load and cognitive impairment have already been proved, further studies are warranted to investigate possible associations between the thrombolytic treatment of patients with AIS, mainly those with baseline CMBs, and the risk of earlier cognitive decline.