Department of Life Sciences, The Open University, Walton Hall, Milton Keynes MK7 6AA, UK.
Brain Behav Immun. 2012 Jul;26(5):778-88. doi: 10.1016/j.bbi.2011.09.013. Epub 2011 Oct 2.
Altered synaptic morphology, progressive loss of synapses and glial (astrocyte and microglial) cell activation are considered as characteristic hallmarks of aging. Recent evidence suggests that there is a concomitant age-related decrease in expression of the presynaptic protein, synaptophysin, and the neuronal glycoprotein CD200, which, by interacting with its receptor, plays a role in maintaining microglia in a quiescent state. These age-related changes may be indicative of reduced neuroglial support of synapses. FG Loop (FGL) peptide synthesized from the second fibronectin type III module of neural cell adhesion molecule (NCAM), has previously been shown to attenuate age-related glial cell activation, and to 'restore' cognitive function in aged rats. The mechanisms by which FGL exerts these neuroprotective effects remain unclear, but could involve regulation of CD200, modifying glial-synaptic interactions (affecting neuroglial 'support' at synapses), or impacting directly on synaptic function. Light and electron microscopic (EM) analyses were undertaken to investigate whether systemic treatment with FGL (i) alters CD200, synaptophysin (presynaptic) and PSD-95 (postsynaptic) immunohistochemical expression levels, (ii) affects synaptic number, or (iii) exerts any effects on glial-synaptic interactions within young (4 month-old) and aged (22 month-old) rat hippocampus. Treatment with FGL attenuated the age-related loss of synaptophysin immunoreactivity (-ir) within CA3 and hilus (with no major effect on PSD-95-ir), and of CD200-ir specifically in the CA3 region. Ultrastructural morphometric analyses showed that FGL treatment (i) prevented age-related loss in astrocyte-synaptic contacts, (ii) reduced microglia-synaptic contacts in the CA3 stratum radiatum, but (iii) had no effect on the mean number of synapses in this region. These data suggest that FGL mediates its neuroprotective effects by regulating glial-synaptic interaction.
突触形态改变、突触逐渐丧失以及神经胶质细胞（星形胶质细胞和小胶质细胞）激活被认为是衰老的特征性标志。最近的证据表明，突触前蛋白突触小体相关蛋白和神经元糖蛋白 CD200 的表达也会伴随年龄的增长而相应减少，它们通过与其受体相互作用，在静息状态下维持小胶质细胞。这些与年龄相关的变化可能表明神经胶质对突触的支持减少。来源于神经细胞黏附分子（NCAM）第二型 III 纤维连接蛋白结构域的 FG 环（FGL）肽先前已被证明可减弱与年龄相关的神经胶质细胞激活，并可“恢复”老年大鼠的认知功能。FGL 发挥这些神经保护作用的机制尚不清楚，但可能涉及 CD200 的调节，改变胶质-突触相互作用（影响突触处的神经胶质“支持”），或直接影响突触功能。进行了光镜和电子显微镜（EM）分析，以研究全身性给予 FGL 是否会：（i）改变 CD200、突触小体相关蛋白（突触前）和 PSD-95（突触后）的免疫组织化学表达水平；（ii）影响突触数量；或（iii）对年轻（4 月龄）和老年（22 月龄）大鼠海马内的胶质-突触相互作用产生任何影响。FGL 处理可减轻 CA3 和门区的突触小体相关蛋白免疫反应性（ir）以及 CA3 区的 CD200-ir 的年龄相关性丧失（对 PSD-95-ir 无主要影响），并减弱了小胶质细胞与突触的接触。超微结构形态计量分析表明，FGL 处理（i）可防止星形胶质细胞-突触接触的年龄相关性丧失；（ii）减少 CA3 放射层的小胶质细胞-突触接触；但（iii）对该区域的突触数量没有影响。这些数据表明，FGL 通过调节胶质-突触相互作用来发挥其神经保护作用。
