Apoptosis of oligodendrocytes in the central nervous system results in rapid focal demyelination

被引:69
作者
Caprariello, Andrew V. [1 ]
Mangla, Saisho [2 ]
Miller, Robert H. [2 ]
Selkirk, Stephen M. [3 ,4 ]
机构
[1] Case Western Reserve Sch Med, Dept Physiol & Biophys, Cleveland, OH USA
[2] Case Western Reserve Sch Med, Dept Neurosci, Cleveland, OH USA
[3] Case Western Reserve Sch Med, Dept Neurol, Cleveland, OH USA
[4] Louis Stokes Cleveland Dept Vet Affairs Med Ctr, Spinal Cord Injury Div, Cleveland, OH USA
关键词
MULTIPLE-SCLEROSIS LESIONS; IN-VIVO; CELL-DEATH; REMYELINATION; MICROGLIA; CLEARANCE; PROTEIN; MODEL; DEGENERATION;
D O I
10.1002/ana.23606
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Objective: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that presents with variable pathologies that may reflect different disease-causing mechanisms. Existing animal models of MS induce pathology using either local injection of gliotoxins or stimulation of the immune system with myelin-related peptides. In none of these models is the primary cellular target well characterized, and although demyelination is a hallmark pathological feature in MS, it is unclear to what extent this reflects local oligodendrocyte loss. To unambiguously identify the effects of oligodendrocyte death in the absence of inflammatory stimulation, we developed a method for experimentally inducing programmed cell death selectively in mature oligodendrocytes and assessed the effects on demyelination, immunological stimulation, and gliosis. The resulting pathology is discussed relative to observed MS pathologies. Methods: Oligodendrocyte apoptosis was induced in the adult rat brain using a lentivirus to express experimentally inducible caspase 9 (iCP9) cDNA under transcriptional control of the promoter for myelin basic protein, which is oligodendrocyte-specific. Activation of iCP9 was achieved by distal injection of a small molecule dimerizer into the lateral ventricle resulting in localized, acute oligodendrocyte apoptosis. Results: Induced oligodendrocyte apoptosis resulted in rapid demyelination and robust, localized microglial activation in the absence of peripheral immune cell infiltration. Lesion borders showed layers of preserved and degraded myelin, whereas lesion cores were demyelinated but only partially cleared of myelin debris. This resulted in local proliferation and mobilization of the oligodendrocyte progenitor pool. Interpretation: This approach provides a novel model to understand the pathological changes that follow from localized apoptosis of myelinating oligodendrocytes. It provides the first direct proof that initiation of apoptosis in oligodendrocytes is sufficient to cause rapid demyelination, gliosis, and a microglial response that result in lesions sharing some pathological characteristics with a subset of MS lesions. ANN NEUROL 2012;72:395405
引用
收藏
页码:395 / 405
页数:11
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