Laboratorio Cajal de Circuitos Corticales (CTB), Universidad Politécnica de Madrid, Campus Montegancedo S/N, 28223 Pozuelo de Alarcón, Spain.
Brain. 2013 Jun;136(Pt 6):1913-28. doi: 10.1093/brain/awt088. Epub 2013 May 28.
The dendritic spines on pyramidal cells represent the main postsynaptic elements of cortical excitatory synapses and they are fundamental structures in memory, learning and cognition. In the present study, we used intracellular injections of Lucifer yellow in fixed tissue to analyse over 19 500 dendritic spines that were completely reconstructed in three dimensions along the length of the basal dendrites of pyramidal neurons in the parahippocampal cortex and CA1 of patients with Alzheimer's disease. Following intracellular injection, sections were immunostained for anti-Lucifer yellow and with tau monoclonal antibodies AT8 and PHF-1, which recognize tau phosphorylated at Ser202/Thr205 and at Ser396/404, respectively. We observed that the diffuse accumulation of phospho-tau in a putative pre-tangle state did not induce changes in the dendrites of pyramidal neurons, whereas the presence of tau aggregates forming intraneuronal neurofibrillary tangles was associated with progressive alteration of dendritic spines (loss of dendritic spines and changes in their morphology) and dendrite atrophy, depending on the degree of tangle development. Thus, the presence of phospho-tau in neurons does not necessarily mean that they suffer severe and irreversible effects as thought previously but rather, the characteristic cognitive impairment in Alzheimer's disease is likely to depend on the relative number of neurons that have well developed tangles.
树突棘是皮质兴奋性突触的主要后突触成分，是记忆、学习和认知的基本结构。在本研究中，我们使用固定组织内的 Lucifer yellow 注射来分析超过 19500 个树突棘，这些树突棘沿着海马旁回皮质和 CA1 区的锥体神经元的基底树突的全长在三维空间中完全重建。在细胞内注射后，对切片进行抗 Lucifer yellow 和 tau 单克隆抗体 AT8 和 PHF-1 的免疫染色，后者分别识别 Ser202/Thr205 和 Ser396/404 磷酸化的 tau。我们观察到，在假定的预缠结状态下磷酸化 tau 的弥散性积累不会引起锥体神经元树突的变化，而形成神经元内神经原纤维缠结的 tau 聚集物与树突棘的渐进性改变（树突棘丢失和形态变化）和树突萎缩有关，这取决于缠结的发展程度。因此，神经元中磷酸化 tau 的存在并不一定意味着它们像以前认为的那样遭受严重和不可逆转的影响，而是阿尔茨海默病的特征性认知障碍可能取决于具有良好发育的缠结的神经元的相对数量。
