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Optimization of Propargylcholine to Label Newly Synthesized Myelin in the Rhesus Monkey Brain

髓鞘 前脑 豪华耐晒蓝 白质 再髓鞘化 髓鞘碱性蛋白 共焦显微镜 神经科学 病理 生物 神经病理学 化学 细胞生物学 中枢神经系统 医学 磁共振成像 疾病 放射科
作者
Karen R. Bottenfield,Tara L. Moore,Farzad Mortazavi,Douglas L. Rosene
出处
期刊:The FASEB Journal [Wiley]
卷期号:34 (S1): 1-1
标识
DOI:10.1096/fasebj.2020.34.s1.03588
摘要

Neuropathology in monkey and human brains often involves loss or damage to myelin and is a major factor impacting normal function as myelin constitutes 35%–40% of the forebrain. Methods to assess alterations in myelin include electron microscopy, histological stains (e.g. Luxol Fast Blue), immunohistochemistry (e.g. for myelin basic protein) and a label free confocal method (SCoRe), as well as diffusion MRI. Each method has advantages but none offer a reliable, validated method to assess microscopic changes in myelin (synthesis or repair) across the entire forebrain from gray matter fascicles to subcortical white matter. Here we present preliminary data that newly synthesized myelin can be detected with in vivo administration of a choline analog, propargylcholine (P‐Cho), that is readily incorporated into all classes of choline phospholipids including major components of the myelin sheath, phosphatidylcholine and sphingomyelin. Importantly, since P‐Cho contains an alkyne moiety, it can be visualized post mortem by conjugation with a fluoro‐labeled azide using click chemistry and detection with confocal microscopy. P‐Cho can be administered by intraperitoneal injection where it enters the circulation and is incorporated into myelin, allowing detection and quantification of newly synthesized myelin. While previous research has demonstrated the use of P‐Cho for assessing remyelination in mice, its efficacy and safety in monkeys has yet to be explored. This is important for our monkey model of normal aging where age‐related myelin pathology accounts for cognitive deficits and for our studies of recovery after damage to the motor cortex. The ability to quantify myelin plasticity in both of these models could provide significant insight into myelin pathology, repair, and maintenance. To test this, we administered P‐Cho daily for 6 days via IP injections (3.5 – 4.0 mg/kg) to 6 young adult and 1 older adult monkey at different time points before euthanasia (1, 2 and 6 weeks). Frozen brain sections were cut, labeled with a fluorescent azide, and the sections evaluated for the presence and specificity of P‐Cho by co‐labeling the tissue with antibodies for axons (SMI‐312) and newly formed actively myelinating oligodendrocytes (BCAS1). Co‐localization of P‐Cho was also performed using confocal reflectance microscopy (SCoRe). Preliminary analyses suggest effective incorporation of P‐Cho into newly synthesized myelin within 1 week of dosing and sustained presence beyond 6 weeks. These results demonstrate a promising new method for investigating remyelination and white matter pathologies related to aging that could also be applied to studies of neurodegeneration, brain injury, and neurological diseases in an animal model highly translatable to humans. Support or Funding Information NIH Grants R01‐AG062831, R01‐AG043640; R01‐AG042512; R21‐AG061678; R21‐NS111174, U01‐NS076474

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