Physiologic Reelin does not play a strong role in protection against acute stroke

Abstract

Stroke and Alzheimer's disease, two diseases that disproportionately affect the aging population, share a subset of pathological findings and risk factors. The primary genetic risk factor after age for late-onset Alzheimer's disease, ApoE4, has also been shown to increase stroke risk and the incidence of post-stroke dementia. One mechanism by which ApoE4 contributes to disease is by inducing in neurons a resistance to Reelin, a neuromodulator that enhances synaptic function. Previous studies in Reelin knockout mice suggest a role for Reelin in protection against stroke; however, these studies were limited by the developmental requirement for Reelin in neuronal migration. To address the question of the effect of Reelin loss on stroke susceptibility in an architecturally normal brain, we utilized a novel mouse with induced genetic reduction of Reelin. We found that after transient middle cerebral artery occlusion, mice with complete adult loss of Reelin exhibited a similar level of functional deficit and extent of infarct as control mice. Together, these results suggest that physiological Reelin does not play a strong role in protection against stroke pathology.

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“…Reelin signaling is reported to regulate microtubule dynamics by binding to ApoER2 receptors and inhibiting GSK-3β activity, which is known to be an important phosphatase of tau (Chai and Frotscher, 2016). In our study, there was no difference on reelin protein and mRNA levels at each time point after reperfusion between Sham group and CIR group, which is in accordance with the recent study (Lane-Donovan et al, 2016). SHD also had no effect on the expression level of reelin in CIR, illustrating that SHD may regulate p-tau level though the downstream molecules of reelin signaling.…”

B cells migrate into remote brain areas and support neurogenesis and functional recovery after focal stroke in mice

“…Each mouse was administered a weekly additional dose of rituximab thereafter to target the turnover of B cells. Successful and sustained B cell depletion was confirmed by isolating lymphocytes from spleen 2 or 8 wk post tMCAo that were stained with a general antibody panel and quantified by flow cytometry (78)(79)(80). B cells were purified from the splenocyte population using magnetic bead separation (Stem Cell Technologies).…”

“…Statistical Analysis. Power analysis based on previous results and published data determined the approximate number of animals given an expected 30% stroke-induced mortality rate (80). Statistical differences were analyzed using unpaired parametric two-sample Student's t test, ratio paired Student's t test, one-way repeated-measures ANOVA, or two-way ANOVA where appropriate and as indicated in the text (Graph Pad Prism 6.0).…”

Impaired meningeal lymphatic vessel development worsens stroke outcome

“…tMCAo was performed as previously described, 11 – 13 with minor modifications, by surgeons blinded to condition. Briefly, animals were anesthetized (2% isoflurane/ 70% NO 2 / 30%O 2 ) and kept warm on a heating pad at 37℃.…”

“…A total of n ¼ 27 mice were included for all PT stroke surgeries, with complete survival and no exclusions. tMCAo tMCAo was performed as previously described, [11][12][13] with minor modifications, by surgeons blinded to condition. Briefly, animals were anesthetized (2% isoflurane/ 70% NO 2 / 30%O 2 ) and kept warm on a heating pad at 37 C. A small incision was made to pull the muscle back from the skull and reveal the middle cerebral artery (MCA) for Doppler flowmetry.…”