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.

中文翻译：

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有毒的tau低聚物的形成受半胱氨酸残基的1,2-二羟基苯基团封端的阻碍。

神经纤维缠结，由高磷酸化的tau原纤维组成，是阿尔茨海默氏病的病理标志。神经原纤维缠结负荷与疾病的临床进展密切相关。越来越多的证据表明，tau低聚物的形成先于神经原纤维缠结的出现，并导致神经元丢失。在这里我们表明，tau低聚物的形成可以被其化学骨架包括1,2-二羟基苯的化合物抑制。具体来说，我们证明含1,2-二羟基苯的化合物结合并封盖tau的半胱氨酸残基，并通过阻碍tau分子之间的相互作用来防止其聚集。此外，我们还显示了口服给药的DL-异丙肾上腺素，一种肾上腺素能受体激动剂，其骨架包括1,2-二羟基苯并能穿透大脑，降低去污剂不溶性tau，神经元丢失的水平，并逆转与神经纤维缠结相关的脑功能障碍。因此，靶向tau的半胱氨酸残基的化合物可能被证明可用于阻止阿尔茨海默氏病和其他tauopathies的进展。