Iqbal Khalid, Alonso Alejandra del C, Grundke-Iqbal Inge
New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314-6399, USA.
J Alzheimers Dis. 2008 Aug;14(4):365-70. doi: 10.3233/jad-2008-14402.
Neurofibrillary degeneration of abnormally hyperphosphorylated tau, a hallmark of Alzheimer's disease (AD) and related tauopathies, occurs both as cytosolic aggregated/oligomeric protein (AD P-tau) and as neurofibrillary tangles. The abnormal hyperphosphorylation not only results in the loss of tau function of promoting assembly and stabilizing microtubules but, in the case of the cytosolic AD P-tau, also in a gain of a toxic function whereby the pathological tau sequesters not only normal tau, but also the other two neuronal microtubule associated proteins (MAPs), MAP1A / MAP1B and MAP2, and causes inhibition and disruption of microtubules. The sequestration of normal MAPs leads to a slow but progressive degeneration of the affected neurons. The affected neurons defend against the toxic tau by continually synthesizing new normal tau as well as by packaging the abnormally hyperphosphorylated tau into polymers, i.e., neurofibrillary tangles of paired helical filaments, twisted ribbons and straight filaments. The filamentous tau is inert; it neither interacts with tubulin and stimulates it assembly, nor binds to normal MAPs and causes disruption of microtubules. These findings suggest the inhibition of tau abnormal hyperphosphorylation and not the aggregation of tau as the preferred therapeutic target for AD and related tauopathies.
异常高度磷酸化的tau蛋白的神经原纤维变性是阿尔茨海默病（AD）及相关tau蛋白病的一个标志，它以胞质聚集/寡聚蛋白（AD P-tau）和神经原纤维缠结的形式出现。异常的高度磷酸化不仅导致tau蛋白促进组装和稳定微管的功能丧失，而且就胞质AD P-tau而言，还导致一种毒性功能的获得，即病理性tau蛋白不仅隔离正常tau蛋白，还隔离另外两种神经元微管相关蛋白（MAPs），即MAP1A / MAP1B和MAP2，并导致微管的抑制和破坏。正常MAPs的隔离导致受影响神经元缓慢但渐进性的变性。受影响的神经元通过持续合成新的正常tau蛋白以及将异常高度磷酸化的tau蛋白包装成聚合物来抵御毒性tau蛋白，即成对螺旋丝、扭曲带和直丝的神经原纤维缠结。丝状tau蛋白是无活性的；它既不与微管蛋白相互作用并刺激其组装，也不与正常MAPs结合并导致微管破坏。这些发现表明，抑制tau蛋白异常高度磷酸化而非tau蛋白聚集是AD及相关tau蛋白病的首选治疗靶点。
