Department of Clinical Neurosciences, University of Calgary, Calgary, AB, T2N 4N1, Canada.
Hotchkiss Brain Institute, University of Calgary, Calgary, AB, T2N 4N1, Canada.
Mol Brain. 2022 Jul 26;15(1):67. doi: 10.1186/s13041-022-00955-2.
As in neurons, CNS myelin expresses N-Methyl-D-Aspartate Receptors (NMDARs) that subserve physiological roles, but have the potential to induce injury to this vital element. Using 2-photon imaging of myelinic Ca in live ex vivo mouse optic nerves, we show that Cu ions potently modulate Ca levels in an NMDAR-dependent manner. Chelating Cu in the perfusate induced a substantial increase in Ca levels, and also caused significant axo-myelinic injury. Myelinic NMDARs are shown to be regulated by cellular prion protein; only in prion protein KO optic nerves does application of NMDA + D-serine induce a large Ca increase, consistent with strong desensitization of these receptors in the presence of prion protein limiting Ca overload. Aβ peptide induced a large Ca increase that was also Cu-dependent, and was blocked by NMDAR antagonism. Our results indicate that like in neurons, myelinic NMDARs permeate potentially injurious amounts of Ca, and are also potently regulated by micromolar Cu and activated by Aβ peptides. These findings shed mechanistic light on the important primary white matter injury frequently observed in Alzheimer's brain.
与神经元一样，中枢神经系统髓鞘表达 N-甲基-D-天冬氨酸受体（NMDAR），这些受体发挥生理作用，但也有可能对这种重要的髓鞘元素造成损伤。通过对活体离体小鼠视神经髓鞘钙的双光子成像，我们发现铜离子以 NMDAR 依赖的方式强烈调节钙水平。在灌流液中螯合铜会引起钙水平的显著增加，并导致明显的轴突-髓鞘损伤。髓鞘 NMDAR 受朊病毒蛋白调节；只有在朊病毒蛋白 KO 视神经中，应用 NMDA+D-丝氨酸才会诱导大量钙增加，这与在朊病毒蛋白存在下这些受体的强烈脱敏一致，从而限制钙超载。Aβ 肽诱导的钙增加也依赖于铜，并且可以被 NMDAR 拮抗剂阻断。我们的结果表明，与神经元一样，髓鞘 NMDAR 允许潜在的有害钙通过，并且还受到微摩尔铜的强烈调节，并被 Aβ 肽激活。这些发现为阿尔茨海默病大脑中经常观察到的重要原发性白质损伤提供了机制上的启示。
