Department of Neuroscience, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
Department of Medicine, Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health & Science University, Portland, OR 97239, USA.
Exp Neurol. 2019 Nov;321:113031. doi: 10.1016/j.expneurol.2019.113031. Epub 2019 Aug 3.
Charcot-Marie-Tooth (CMT) diseases comprise a genetically heterogeneous group of hereditary peripheral neuropathies. Trembler J (TrJ) mice carry a spontaneous mutation in peripheral myelin protein 22 (PMP22) and model early-onset, severe CMT type 1E disease. Recent studies indicate that phospholipid substitution, or cholesterol-enriched diet, benefit myelinated nerves, however such interventions have not been tested in early-onset dysmyelinating neuropathies. Here, we examined the lipid profile of peripheral nerves from 6-month-old TrJ mice with advanced neuropathy and tested the impact of a 6-week-long neutral lipid-enriched high-fat diet (HFD) on neuropathy progression in young, newly-weaned mice. Oil Red O staining showed pronounced neutral lipid accumulation in nerves from 6-month-old TrJ mice, along with elevated levels of key cholesterol and triglyceride transport proteins including apoE, LRP1 and ABCA1, compared with wild type (Wt). In young mice, the short-term HFD intervention increased serum cholesterol levels without impacting triglycerides, or body and liver weights. Tissue samples from neuropathic TrJ mice showed improvements in the maintenance of myelinated axons after the 6-week-long dietary intervention, and this effect was evident both in the sciatic and phrenic nerves. Concomitantly, aberrant Schwann cell proliferation was attenuated, as detected by reduction in mitotic markers and in c-Jun expression. Nerves from HFD-fed TrJ mice contained fewer macrophages, with a normalized count of CD11b + cells. In addition, we detected an increase in neutral lipids in the nerve endoneurium and a trend toward normalization of apoE, LRP1, and ABCA1 expression after the HFD feeding. Together, these results demonstrate the beneficial influence of a short-term neutral lipid-enriched diet on neuropathy progression in young TrJ mice and support further work in investigating the potential benefits of dietary lipids on hereditary neuropathies.
Charcot-Marie-Tooth (CMT) 疾病是一组遗传性周围神经病，具有遗传异质性。 Trembler J (TrJ) 小鼠携带外周髓鞘蛋白 22 (PMP22) 的自发性突变，可模拟早发性、严重的 CMT1E 疾病。最近的研究表明，磷脂替代或富含胆固醇的饮食有益于有髓神经，但这些干预措施尚未在早发性脱髓鞘神经病中进行测试。在这里，我们检查了处于晚期神经病变的 6 个月大的 TrJ 小鼠周围神经的脂质谱，并测试了富含中性脂质的高脂肪饮食 (HFD) 对幼鼠新断奶时神经病变进展的影响。油红 O 染色显示，与野生型 (Wt) 相比，6 个月大的 TrJ 小鼠的神经中存在明显的中性脂质积累，以及关键胆固醇和甘油三酯转运蛋白（包括 apoE、LRP1 和 ABCA1）水平升高。在幼鼠中，短期 HFD 干预增加了血清胆固醇水平，而不影响甘油三酯或体重和肝脏重量。来自神经病变 TrJ 小鼠的组织样本显示，在 6 周的饮食干预后，维持有髓轴突的效果得到改善，这种效果在坐骨神经和膈神经中都很明显。同时，通过减少有丝分裂标志物和 c-Jun 表达，减弱了异常 Schwann 细胞增殖。HFD 喂养的 TrJ 小鼠的神经中巨噬细胞较少，CD11b+细胞计数正常。此外，我们在神经内膜中检测到中性脂质增加，并在 HFD 喂养后 apoE、LRP1 和 ABCA1 的表达有正常化趋势。总之，这些结果表明，富含中性脂质的短期饮食对幼鼠 TrJ 神经病变进展有有益影响，并支持进一步研究饮食脂质对遗传性神经病的潜在益处。
