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脑是人体的指挥官,其内各种神经环路控制着人的行为、认知和情感。在环路中,除了神经元胞体、树突和轴突、突触等结构,髓鞘也在其中起到了至关重要的作用。

髓鞘,不仅是环路的绝缘层

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脑是人体的指挥官,其内各种神经环路控制着人的行为、认知和情感。在环路中,除了神经元胞体、树突和轴突、突触等结构,髓鞘也在其中起到了至关重要的作用。

髓鞘由成熟的少突胶质细胞形成,包裹于轴突表面,就像电线表面的绝缘层,起到了相邻轴突间电气绝缘、加快动作电位传递及引导轴突再生的作用。灵长类动物少突质细胞的髓鞘化过程在出生后逐渐完成,感觉运动区最先完成,持续至20 岁左右前额叶和顶叶可持续至50 岁后,颞叶尤其是基底部和海马旁回区甚至可持续至60岁后,其过程与人类行为功能和认知功能的发育顺序相符。在老龄化的过程中,中枢神经系统髓鞘化纤维丢失、髓鞘化轴突数目减少、总长度缩短髓鞘破坏导致神经元电传导受阻,长距离脑区间同步性受损,并可引起突前膜蛋白成分的变;重损伤会导致轴突突前蛋白传递受阻、轴突的异常发生和退行性变,损害认知功能,并逐步过渡到运动功能,恰恰与发育获顺序相反。多种神经系统疾病,如多发性硬化、弥漫性硬化等,存在髓鞘损害,同时伴有认知功能的损害;最近研究发现,精神分裂症、抑郁症、双相情感障碍等具有情感认知功能障碍的精神疾病,均有髓鞘损害证据,疾病中情感和认知功能的减退可能与髓鞘损害有关

由上可知,髓鞘的损害可以导致神经信号的传导改变并最终影响神经环路功能。而在201452日,斯坦福大学Michelle Monje的团队在Science发表的一篇研究发现,在神经环路中,神经元的活动可以影响髓鞘的形成和修复,进而影响环路的功能。研究人员借助光遗传学技术,在体刺激小鼠单侧前运动皮层第五层神经元,发现可以提升少突胶质细胞的增殖、分化并使得髓鞘增厚。在持续刺激该运动皮层四周之后,这一系列髓鞘的自适应变化最终提升了相关肢体的运动能力。这一研究的意义在于不仅从机制上证实了髓鞘可塑性的变化可以导致疾病的发生,而且也为今后神经环路相关疾病的研究开辟了新的道路。髓鞘这一环路中并不起眼的绝缘层,正越来越受到人们的关注。


相关的四篇文章:

1.

论文标题:AnAlzheimer’sDisease-relevant Presenilin-1 MutationAugments Amyloid-beta-induced OligodendrocyteDysfunction

   

原文摘要:White matter pathology has beendocumented in the brains of familial Alzheimers disease (FAD)-afflictedindividuals during pre-symptomatic and pre-clinical stages of AD. How thesedefects inmyelinationintegrity arise and what roles they may play in AD pathophysiology have yet tobefully elucidated. We previouslydemonstrated that triple-transgenic AD (3xTg-AD) mice, whichharbor the human amyloidprecursor Swedish mutation, presenilin-1 M146V (PS1M146V ) knock-inmutation, and tauP301L mutation,exhibit myelin abnormalities analogous to FAD patients and thatAβ1–42 contributes to thesewhite matter deficits. Herein, we demonstrate that the PS1M146Vmutation predisposes mouseoligodendrocyte precursor (mOP) cells to Aβ1–42-induced alterationsin cell differentiation in vitro. Furthermore, PS1M146V expressioncompromised mOP cell functionandMBP protein distribution, a process that is further aggravated with exposure toAβ1–42. Wefoundthat the myelination defect and MBP subcellular mislocalization triggered byPS1M146V andAβ1–42can be effectively prevented by treatment with the GSK-3βinhibitor, TWS119,therebyimplicatingGSK-3βkinase activity in this pathogenic cascade. Overall, this work providesfurthermechanisticinsights into PS1M146V and Aβ1–42-driven oligodendrocyte dysfunction and myelindamage during earlypre-symptomatic stages of AD, and provides a new target inoligodendrocytes for developingtherapies designed to avert AD-related white matter pathology.

 

全文链接:http://www.doc88.com/p-2844357358698.html

 

2.

论文标题:Oligodendrocytes are a Novel Source of AmyloidPeptideGeneration

 

原文摘要:Abstract Alzheimer’s diseaseis characterised by regional neuronal degeneration, synaptic loss, and theprogressive deposition of the 4 kDa β-amyloid peptide (Aβ) in senile plaquesand accumulation of tau protein as neurofibrillary tangles. Aβ derives from thelarger precursor molecule, amyloid precursor protein (APP) by proteolyticprocessing via β- and γ-secretases. While APP expression is well documented inneurons and astrocytes, the case for oligodendrocytes is less clear. The lattercell type is reported to express different isoforms of APP, and we haveconfirmed this observation by immunocytochemistry in cultures of differentiatedrat cortical oligodendrocytes. Moreover, by means of a sensitiveelectrochemiluminescent immunoassay employing Aβ C-terminal specificantibodies, mature oligodendrocytes are shown to secrete the 40 and 42 aminoacid Aβ species (Aβ40 and Aβ42). Secretion of Aβ peptides was reduced byincubating oligodendrocytes with α- and β-secretase inhibitors, or aγ-secretase inhibitor. Disturbances of APP processing and/ or synthesis inoligodendrocytes may account for some myelin disorders observed in Alzheimer\'sdisease and other senile dementias.

全文链接:http://link.springer.com/article/10.1007/s11064-009-0022-9

 

3.

论文标题:Amyloidβ1-42 oligomer inhibits myelin sheet formation in vitro

 

原文摘要:Accumulatingevidence indicates that white matter degeneration contributes to the neuraldisconnections that underlie Alzheimer’s disease pathophysiology. Although thiswhite matter degeneration is partly attributable to axonopathy associated withneuronal degeneration, amyloid β (Aβ) protein-mediated damageto oligodendrocytes could be another mechanism. To test this hypothesis, westudied effects of soluble Aβ in oligomeric form on survival anddifferentiation of cells of the oligodendroglial lineage using highly purifiedoligodendroglial cultures from rats at different developmental stages. Aβoligomer at 10 μM or higher reduced survival of matureoligodendrocytes, whereas oligodendroglial progenitor cells (OPCs) wererelatively resistant to the Aβ oligomer-mediated cytotoxicity. Furtherstudy revealed that Aβ oligomer even at 1 μM accelerated3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) formazan exocytosisin mature oligodendrocytes, and, more significantly, inhibited myelin sheetformation after induction of in vitro differentiation of OPCs. These resultsimply a novel pathogenetic mechanism underlying Aβ oligomer-mediatedwhite matter degeneration, which could impair myelin maintenance andremyelination by adult OPCs, resulting in accumulating damage to myelinatingaxons thereby contributing to neural disconnections.

 

原文链接:http://europepmc.org/articles/PMC3013291/

 

4.

原文标题Neuronal Activity Promotes OligodendrogenesisandAdaptiveMyelinationin the Mammalian Brain

 

原文摘要:Myelination of thecentral nervous system requires the generation of functionally matureoligodendrocytes from oligodendrocyte precursor cells (OPCs). Electricallyactive neurons may influence OPC function and selectively instruct myelinationof an active neural circuit. In this work, we use optogenetic stimulation ofthe premotor cortex in awake, behaving mice to demonstrate that neuronalactivity elicits a mitogenic response of neural progenitor cells and OPCs,promotes oligodendrogenesis, and increases myelination within the deep layersof the premotor cortex and subcortical white matter. We further show that thisneuronal activity-regulated oligodendrogenesis and myelination is associatedwith improved motor function of the corresponding limb. Oligodendrogenesis andmyelination appear necessary for the observed functional improvement, asepigenetic blockade of oligodendrocyte differentiation and myelin changesprevents the activity-regulated behavioral improvement.

 

原文链接:http://europepmc.org/articles/pmc4096908