Hanger Diane P, Lau Dawn H W, Phillips Emma C, Bondulich Marie K, Guo Tong, Woodward Benjamin W, Pooler Amy M, Noble Wendy
Department of Neuroscience, King's College London, Institute of Psychiatry, De Crespigny Park, London, UK.
J Alzheimers Dis. 2014;40 Suppl 1:S37-45. doi: 10.3233/JAD-132054.
Tau has a well-established role as a microtubule-associated protein, in which it stabilizes the neuronal cytoskeleton. This function of tau is influenced by tau phosphorylation state, which is significantly increased in Alzheimer's disease and related tauopathies. Disruptions to the cytoskeleton in disease-affected neurons include reduced length and numbers of stable microtubules, and their diminished stability is associated with increased tau phosphorylation in disease. Tau is also localized in the nucleus and plasma membrane of neurons, where it could have roles in DNA repair and cell signaling. Most recently, potential roles for extracellular tau have been highlighted. The release of tau from neurons is a physiological process that can be regulated by neuronal activity and extracellular tau may play a role in inter-neuronal signaling. In addition, recent studies have suggested that the misfolding of tau in diseased brain leads to abnormal conformations of tau that can be taken up by neighboring neurons. Such a mechanism may be responsible for the apparent prion-like spreading of tau pathology through the brain, which occurs in parallel with clinical progression in the tauopathies. The relationship between tau localization in neurons, tau release, and tau uptake remains to be established, as does the function of extracellular tau. More research is needed to identify disease mechanisms that drive the release and propagation of pathogenic tau and to determine the impact of extracellular tau on cognitive decline in neurodegenerative disease.
tau蛋白作为一种微管相关蛋白，其作用已得到充分证实，它能稳定神经元细胞骨架。tau蛋白的这一功能受tau蛋白磷酸化状态的影响，在阿尔茨海默病及相关tau蛋白病中，tau蛋白磷酸化水平显著升高。疾病影响的神经元中细胞骨架的破坏包括稳定微管的长度和数量减少，其稳定性降低与疾病中tau蛋白磷酸化增加有关。tau蛋白也定位于神经元的细胞核和质膜，在DNA修复和细胞信号传导中可能发挥作用。最近，细胞外tau蛋白的潜在作用受到了关注。tau蛋白从神经元的释放是一个可受神经元活动调节的生理过程，细胞外tau蛋白可能在神经元间信号传导中发挥作用。此外，最近的研究表明，患病大脑中tau蛋白的错误折叠会导致tau蛋白异常构象，可被邻近神经元摄取。这种机制可能是tau蛋白病理在大脑中类似朊病毒样传播的原因，这种传播与tau蛋白病的临床进展同时发生。tau蛋白在神经元中的定位、释放和摄取之间的关系以及细胞外tau蛋白的功能仍有待确定。需要更多的研究来确定驱动致病性tau蛋白释放和传播的疾病机制，并确定细胞外tau蛋白对神经退行性疾病认知衰退的影响。
