Stability of the distribution of spines containing drebrin A in the sensory cortex layer I of mice expressing mutated APP and PS1 genes
Stability of the distribution of spines containing drebrin A in the sensory cortex layer I of mice expressing mutated APP and PS1 genes
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DOI：
10.1016/j.brainres.2005.10.012
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发表时间：
2005-12
期刊：
影响因子：
2.9
通讯作者：
Veeravan Mahadomrongkul;P. Huerta;T. Shirao;C. Aoki
中科院分区：
文献类型：
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作者：
Veeravan Mahadomrongkul;P. Huerta;T. Shirao;C. Aoki
被诊断患有阿尔茨海默病 (AD) 的患者死后皮质中的树突蛋白（一种树突棘和轴的 F-肌动蛋白结合蛋白）水平降低。我们使用家族性 AD (FAD) 小鼠模型来确定参与不对称（可能是兴奋性）突触并含有 drebrin A 的皮质棘密度是否降低，如果是，则这种情况是否发生在 β 淀粉样蛋白沉积物出现之前，此时仅存在可溶性 β 淀粉样蛋白 (Aβ)。定量电镜免疫细胞化学显示，到 6 个月时，与 WT 小鼠的相应区域相比，FAD 模型小鼠体感皮层 I 内含有 Drebrin A 的突触后棘的比例较小 (P < 0.0005)。然而，对于两种基因型，含有drebrin A的突触后棘的面密度在3至18个月及更长时间内相对恒定，表明drebrin A赋予突触后棘稳定性。进一步的测量证实，6个月时FAD小鼠大脑中含有drebrin A的棘的比例减少是由于缺乏drebrin A的棘轮廓的尺寸和面密度更大。因此，可溶性Aβ对缺乏drebrin A的棘的影响比含有drebrin A的棘更强烈。在6个月及以上时，与WT小鼠相比，2xKI小鼠中更大比例的棘drebrin A位于突触膜附近。这种模式可能反映了棘内突触分子运输的改变，这是导致突触功能和可塑性下降的一个因素。
Post-mortem cortices from patients diagnosed with Alzheimer's disease (AD) exhibit reduced levels of drebrin, an F-actin binding protein of dendritic spines and shafts. We used a mouse model of familial AD (FAD) to determine whether the density of cortical spines engaged in asymmetric (presumably excitatory) synapses and containing drebrin A is reduced and if so, whether this occurs prior to the emergence of β amyloid deposits, when only soluble β amyloid (Aβ) is present. Quantitative electron microscopic immunocytochemistry revealed that by 6 months, the proportion of postsynaptic spines with drebrin A within somatosensory cortex layer I was smaller for the FAD model mice, when compared to the corresponding region of WT mice (P < 0.0005). However, the areal density of postsynaptic spines containing drebrin A was relatively constant from 3 to 18 months and beyond for both genotypes, suggesting that drebrin A confers stability to postsynaptic spines. Further measurements confirmed that the reduced proportion of drebrin A-containing spines in brains of FAD mice at 6 months is due to the greater size and areal density of spine profiles lacking drebrin A. Thus, soluble Aβ could affect spines lacking drebrin A more strongly than spines containing drebrin A. At 6 months and older, a larger fraction of spinous drebrin A in 2xKI mice was located near the synaptic membrane, as compared to those of WT mice. This pattern may reflect an altered trafficking of synaptic molecules within spines, a factor adding to the decline of synaptic function and plasticity.