TY - JOUR
T1 - A neutral lipid-enriched diet improves myelination and alleviates peripheral nerve pathology in neuropathic mice
AU - Zhou, Ye
AU - Bazick, Hannah
AU - Miles, Joshua R.
AU - Fethiere, Alexander I.
AU - Salihi, Mohammed Omar Al
AU - Fazio, Sergio
AU - Tavori, H.
AU - Notterpek, L.
N1 - Funding Information:
These studies were supported, in part, by funds from the Facial Pain Research Foundation and the UF College of Medicine to L.N. We thank Hong Yi at the Emory University Robert P. Apkarian Integrated Electron Microscopy Core for sample processing and Toluidine blue staining. Studies at OHSU were partially supported by NIH grant HL57986 to S.F and by AHA grant 16SDG27520011 to H.T.
Publisher Copyright:
© 2019 The Authors
PY - 2019/11
Y1 - 2019/11
N2 - 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.
AB - 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.
KW - Cholesterol
KW - Lipid-enriched diet
KW - Macrophage
KW - Peripheral myelin protein 22
KW - Peripheral neuropathy
KW - Trembler J mice
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U2 - 10.1016/j.expneurol.2019.113031
DO - 10.1016/j.expneurol.2019.113031
M3 - Article
C2 - 31386828
AN - SCOPUS:85070388558
VL - 321
JO - Neurodegeneration
JF - Neurodegeneration
SN - 0014-4886
M1 - 113031
ER -