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. 2016 Jul;36(7):1295-303.
doi: 10.1177/0271678X16646386. Epub 2016 May 4.

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

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

Courtney Lane-Donovan et al. J Cereb Blood Flow Metab. 2016 Jul.

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.

Keywords: ApoE4; Reelin; Reelin conditional knockout; stroke; transient middle cerebral artery occlusion.

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Figures

Figure 1.
Figure 1.
tMCAo timeline and confirmation of Reelin knockout. (a) Experimental timeline. All mice were injected with tamoxifen for five days; 16 days later the mice were trained on the rotarod. A 45-min tMCAo was induced after an additional 10 days. Two days later, mice were tested on the rotarod prior to sacrifice. (b) Reelin levels are negligible in Reelin cKO (Cre+) mice (n = 13 Cre− and n = 11 Cre + animals) in post-stroke cerebella.
Figure 2.
Figure 2.
Reelin loss has no significant effect on size of infarct post-tMCAo. (a) Representative brain sections from control (Cre−) and cKO (Cre+) mice two days after tMCAo. (b) Quantification of indirect stroke volume (control: 44.59 ± 6.86 mm3, n = 13; cKO: 36.00 ± 7.80 mm3, n = 11; p = 0.4157) and edema (control: −1.49 ± 1.32%, n = 13; cKO: 0.75 ± 1.71% n = 11; p = 0.3046). Data are represented as mean ± S.E.M.
Figure 3.
Figure 3.
Reelin cKO mice do not have significantly increased functional deficit over control mice following tMCAo. (a) Control and cKO mice showed a similar impairment in motor function during the tMCAO (control: 1.95 ± 0.138, n = 10; cKO 1.91 ± 0.375; Mann–Whitney p = 0.9936). (b) Both genotypes also had a similar impairment two days following tMCAo (control: 1.29 ± 0.258, n = 12; cKO 1.46 ± 0.416; Mann–Whitney p = 0.3667). (c) Control and cKO mice exhibited a similar rotarod ability two days post-tMCAo (control: 57.07 ± 9.51 s, n = 13; cKO: 47.96 ± 10.30 s, n = 11; unpaired t-test p = 0.9703). Data are represented as mean ± S.E.M.
Figure 4.
Figure 4.
No obvious difference in brain anatomy, vasculature, and intrinsic pathophysiology between control and cKO mice. (a) and (c) cresyl violet staining; (b) and (d) alkaline phosphatase staining of control (a and c) and cKO (b and d) brain sections. (e–h) control and cKO mice had similar cerebral flow by Doppler flowmetry before occlusion (e) control: 692.1 a.u., cKO: 761.6 a.u., p = 0.243), immediately after occlusion (f) control: 72.3 a.u., cKO: 78.1 a.u., p = 0.721), prior to suture removal (g) control: 56.0 a.u., cKO: 63.0 a.u., p = 0.612), and after restoration of MCA flow (h) control: 651.5 a.u., cKO: 690.3 a.u., p = 0.666). Data are represented as mean ± S.E.M.

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