Arendt Thomas
Paul Flechsig Institute of Brain Research, Department of Neuroanatomy, Jahnallee 59, D-04109 Leipzig, Germany.
Int J Dev Neurosci. 2004 Nov;22(7):507-14. doi: 10.1016/j.ijdevneu.2004.07.007.
Neurofibrillary degeneration, associated with the formation of paired helical filaments (PHF), is one of the critical neuropathological hallmarks of Alzheimer's disease (AD). Although the microtubule-associated protein tau in a hyperphosphorylated form has been established as primary PHF constituent, the process of tau phosphorylation and its potential link to degeneration is not very well understood, mostly because of the lack of a physiological in vivo model of PHF-like tau phosphorylation. PHF formation in AD follows a hierarchical pattern of development throughout different cortical areas, which closely matches the pattern of neuronal plasticity in the adult brain. Those brain areas are most early and most severely affected which are involved in the regulation of memory, learning, perception, self-awareness, consciousness, and higher brain functions that require a life-long re-fitting of connectivity, a process based on a particularly high degree of plasticity. Failures of synaptic plasticity are, thus, assumed to represent early events in the course of AD that eventually lead to alteration of tau phosphorylation. Recently, we have used the hibernation cycle, a physiological model of adaptation associated with an extraordinary high degree of structural neuronal plasticity, to analyze the potential link between synaptic plasticity, synaptic detachment and the regulation of tau phosphorylation. During torpor, a natural state of hypothermia, synaptic contacts between mossy fibers and hippocampal pyramidal neurons undergo dramatic regressive changes that are fully reversible very rapidly during euthermy. This rapid, reversible, and repeated regression of synaptic and dendritic components on CA3 neurons is associated with a reversible PHF-like phosphorylation of tau at a similar time course. The repeated formation and degradation of PHF-tau might, thus, represent a physiological mechanism not necessarily associated with pathological effects. These findings implicate an essential link between neuronal plasticity and PHF-like phosphorylation of tau, potentially involved in neurofibrillary degeneration.
与双螺旋丝（PHF）形成相关的神经原纤维变性是阿尔茨海默病（AD）关键的神经病理学特征之一。尽管已确定高度磷酸化形式的微管相关蛋白tau是PHF的主要成分，但tau磷酸化过程及其与变性的潜在联系尚未完全明确，主要原因是缺乏类似PHF的tau磷酸化的生理性体内模型。AD中PHF的形成在不同皮质区域遵循分层发展模式，这与成人大脑神经元可塑性模式密切匹配。那些参与记忆、学习、感知、自我意识、意识以及需要终身重新调整连接性（基于特别高程度的可塑性的过程）的高级脑功能调节的脑区最早且受影响最严重。因此，突触可塑性的失败被认为是AD病程中的早期事件，最终导致tau磷酸化改变。最近，我们利用冬眠周期（一种与极高程度的神经元结构可塑性相关的生理适应模型）来分析突触可塑性、突触脱离与tau磷酸化调节之间的潜在联系。在蛰伏期（一种自然的低温状态），苔藓纤维与海马锥体神经元之间的突触接触会发生显著的退行性变化，在正常体温期间这些变化能非常迅速地完全逆转。CA3神经元上突触和树突成分的这种快速、可逆且反复的退行与tau在相似时间进程的可逆性PHF样磷酸化相关。因此，PHF - tau的反复形成和降解可能代表一种不一定与病理效应相关的生理机制。这些发现暗示了神经元可塑性与tau的PHF样磷酸化之间的重要联系，这可能与神经原纤维变性有关。
