Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, Zurich, CH-8057, Switzerland.
Acta Neuropathol Commun. 2013 Jun 26;1:27. doi: 10.1186/2051-5960-1-27.
Reelin and its downstream signaling members are important modulators of actin and microtubule cytoskeleton dynamics, a fundamental prerequisite for proper neurodevelopment and adult neuronal functions. Reductions in Reelin levels have been suggested to contribute to Alzheimer's disease (AD) pathophysiology. We have previously reported an age-related reduction in Reelin levels and its accumulation in neuritic varicosities along the olfactory-limbic tracts, which correlated with cognitive impairments in aged mice. Here, we aimed to investigate whether a similar Reelin-associated neuropathology is observed in the aged human hippocampus and whether it correlated with dementia status.
Our immunohistochemical stainings revealed the presence of N- and C-terminus-containing Reelin fragments in corpora amylacea (CAm), aging-associated spherical deposits. The density of these deposits was increased in the molecular layer of the subiculum of AD compared to non-demented individuals. Despite the limitation of a small sample size, our evaluation of several neuronal and glial markers indicates that the presence of Reelin in CAm might be related to aging-associated impairments in neuronal transport leading to accumulation of organelles and protein metabolites in neuritic varicosities, as previously suggested by the findings and discussions in rodents and primates.
Our results indicate that aging- and disease-associated changes in Reelin levels and proteolytic processing might play a role in the formation of CAm by altering cytoskeletal dynamics. However, its presence may also be an indicator of a degenerative state of neuritic compartments.
Reelin 及其下游信号成员是肌动蛋白和微管细胞骨架动力学的重要调节剂，这是神经发育和成年神经元功能的基本前提。 Reelin 水平的降低被认为有助于阿尔茨海默病（AD）的病理生理学。我们之前报道了 Reelin 水平随年龄的降低及其在嗅-边缘束中的神经突小球中的积累，这与老年小鼠的认知障碍相关。在这里，我们旨在研究在老年人类海马体中是否观察到类似的 Reelin 相关神经病理学，以及它是否与痴呆状态相关。
我们的免疫组织化学染色显示，存在于细胞淀粉体（CAm）中的 N 端和 C 端含有 Reelin 片段，这是与年龄相关的球形沉积物。与非痴呆个体相比，AD 患者的 subiculum 分子层中这些沉积物的密度增加。尽管样本量较小，但我们对几种神经元和神经胶质标志物的评估表明，CAm 中 Reelin 的存在可能与衰老相关的神经元运输受损有关，导致神经突小球中细胞器和蛋白质代谢物的积累，正如之前在啮齿动物和灵长类动物中的发现和讨论所表明的那样。
我们的结果表明，衰老和疾病相关的 Reelin 水平和蛋白水解加工变化可能通过改变细胞骨架动力学在 CAm 的形成中发挥作用。然而，其存在也可能是神经突区退化状态的指标。
