Increase in Mitochondrial Density Within Axons and Supporting Cells in Response to Demyelination in the Plp1 Mouse Model
Increase in Mitochondrial Density Within Axons and Supporting Cells in Response to Demyelination in the Plp1 Mouse Model
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DOI：
10.1002/jnr.21867
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发表时间：
2009-02-01
影响因子：
4.2
通讯作者：
Nichols, Philip
中科院分区：
文献类型：
--
作者：
Hogan, Vanessa;White, Kathryn;Nichols, Philip
我们使用 Plp1 过表达转基因小鼠模型来研究轴突进行性脱髓鞘是否会导致涉及轴突内线粒体的适应性变化。这些模型从出生起就有髓鞘轴突，但逐渐失去髓磷脂，并出现与进行性神经功能障碍相关的轴突损失，类似于继发性进行性多发性硬化症 (SPMS) 患者。在1个月和2个月时，电子显微镜显示与野生型相比，纯合系72 Plp1过表达小鼠的轴突内线粒体密度显着增加（1.43 +/- 0.31 vs. 0.84 +/- 0.16 mu m(-3)，p = 0.031；1.66 +/- 0.11 vs. 0.92 +/- 0.43 mu m(-3)，P = 0.02），并且在同一小鼠中，周围细胞中线粒体密度在 1 个月和 4 个月时显着增加（1.86 +/- 0.31 与 0.81 +/- 0.30 mu m(-3)，P = 0.006；2.77 +/- 0.44 与 1.37 +/- 0.42 mu m(-3)，p = 0.016）。在第 1 个月和第 4 个月，COX 组织化学和延时组织化学显示，与野生型相比，纯合 Plp1 过表达小鼠视神经的线粒体活性和线粒体活性率显着增加（112.37 +/- 11.9 vs. 136.89 +/- 9.1 MeanD，P = 0.006；128.02 +/- 3.0 vs. 128.02 +/- 3.0）。 188.77 +/- 9.7 MeanD P < 0.001；比率 -0.78 +/- 0.25 与 -0.58 +/- 0.15 MeanD Min(-1)，P < 0.001；-1.48 +/- 0.15 与 0.51 +/- 0.17 MeanD Min(-1)，P < 0.001。我们认为，在 Plp1 过表达小鼠的中枢神经系统轴突内发生涉及线粒体的适应性变化，这可能不利于长期生存。 MS 病变中慢性脱髓鞘轴突发生的类似变化可能是增加 SPMS 轴突脆弱性的一种机制。 (c) 2008 年 Wiley-Liss, Inc.
We used the Plp1-overexpressing transgenic mouse model to investigate whether progressive demyelination of axons results in adaptive changes involving mitochondria within the axons. These models have myelinated axons from birth but gradually lose myelin and develop axonal loss associated with progressive neurological disability analogous to patients with secondary progressive mulltiple sclerosis (SPMS). At 1 and 2 months, electron microscopy demonstrated a significant increase in intraaxonal mitochondrial density in the homozygous line 72 Plp1-overexpressing mice compared with wild type (1.43 +/- 0.31 vs. 0.84 +/- 0.16 mu m(-3), p = 0.031; 1.66 +/- 0.11 vs. 0.92 +/- 0.43 mu m(-3), P = 0.02) and a significant increase at 1 and 4 months in the density of mitochondria in the surrounding cells in the same mice (1.86 +/- 0.31 vs. 0.81 +/- 0.30 mu m(-3), P = 0.006; 2.77 +/- 0.44 vs. 1.37 +/- 0.42 mu m(-3), p = 0.016). At both 1 and 4 months, COX histochemistry and time-lapse histochemistry demonstrated a significant increase in mitochondrial activity and rate of mitochondrial activity in the homozygous Plp1-overexpressing mouse optic nerve compared with the wild type (112.37 +/- 11.9 vs. 136.89 +/- 9.1 MeanD, P = 0.006; 128.02 +/- 3.0 vs. 188.77 +/- 9.7 MeanD P < 0.001; Rate -0.78 +/- 0.25 vs. -0.58 +/- 0.15 MeanD Min(-1), P < 0.001; -1.48 +/- 0.15 vs. 0.51 +/- 0.17 MeanD Min(-1), P < 0.001, respectively). We propose that adaptive changes involving mitochondria occur within CNS axons in Plp1 overexpressing mice, which may be detrimental to long-term viability. Analogous changes occurring in chronically demyelinated axons in MS lesions would be one mechanism increasing axonal vulnerability in SPMS. (c) 2008 Wiley-Liss, Inc.