Toxic tau oligomer formation blocked by capping of cysteine residues with 1,2-dihydroxybenzene groups.

Neurofibrillary tangles, composed of hyperphosphorylated tau fibrils, are a pathological hallmark of Alzheimer's disease; the neurofibrillary tangle load correlates strongly with clinical progression of the disease. A growing body of evidence indicates that tau oligomer formation precedes the appearance of neurofibrillary tangles and contributes to neuronal loss. Here we show that tau oligomer formation can be inhibited by compounds whose chemical backbone includes 1,2-dihydroxybenzene. Specifically, we demonstrate that 1,2-dihydroxybenzene-containing compounds bind to and cap cysteine residues of tau and prevent its aggregation by hindering interactions between tau molecules. Further, we show that orally administered DL-isoproterenol, an adrenergic receptor agonist whose skeleton includes 1,2-dihydroxybenzene and which penetrates the brain, reduces the levels of detergent-insoluble tau, neuronal loss and reverses neurofibrillary tangle-associated brain dysfunction. Thus, compounds that target the cysteine residues of tau may prove useful in halting the progression of Alzheimer's disease and other tauopathies. Aggregation of microtubule associated protein tau is one of cause of neuronal loss in tauopathies including Alzheimer's disease. Here, the authors show that compounds with a 1,2-dihydroxybenzene skeleton can modify cysteine residues in tau and block toxic tau aggregation.

由过度磷酸化的tau纤维构成的神经原纤维缠结是阿尔茨海默病的一个病理特征；神经原纤维缠结的负荷与该疾病的临床进展密切相关。越来越多的证据表明，tau寡聚体的形成先于神经原纤维缠结的出现，并导致神经元丢失。在此我们表明，化学主链包含1,2 - 二羟基苯的化合物能够抑制tau寡聚体的形成。具体而言，我们证明含1,2 - 二羟基苯的化合物与tau的半胱氨酸残基结合并封闭它们，通过阻碍tau分子之间的相互作用来防止其聚集。此外，我们表明口服给予的DL - 异丙肾上腺素（一种骨架包含1,2 - 二羟基苯且能穿透大脑的肾上腺素能受体激动剂）可降低去污剂不溶性tau的水平、减少神经元丢失并逆转与神经原纤维缠结相关的脑功能障碍。因此，靶向tau半胱氨酸残基的化合物可能在阻止阿尔茨海默病和其他tau蛋白病的进展方面是有用的。 微管相关蛋白tau的聚集是包括阿尔茨海默病在内的tau蛋白病中神经元丢失的原因之一。在此，作者表明具有1,2 - 二羟基苯骨架的化合物能够修饰tau中的半胱氨酸残基并阻断有毒的tau聚集。