Noble Wendy, Garwood Claire, Stephenson John, Kinsey Anna M, Hanger Diane P, Anderton Brian H
MRC Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry, Department of Neuroscience, PO37, De Crespigny Park, London, SE5 8AF, UK.
FASEB J. 2009 Mar;23(3):739-50. doi: 10.1096/fj.08-113795. Epub 2008 Nov 11.
Alzheimer's disease (AD) is characterized by the presence of neurofibrillary tangles of hyperphosphorylated, aggregated tau protein and extracellular deposits of beta-amyloid peptide. Increased beta-amyloid levels are thought to precede tangle formation, but tau pathology is more closely related to neuronal death. Minocycline, a tetracycline derivative, has potent antiinflammatory, antiapoptotic, and neuroprotective effects in several models of neurodegenerative disease, including models of AD with amyloid pathology. We have used both in vitro and in vivo models of AD to determine whether minocycline may have therapeutic efficacy against tau pathology. In primary cortical neurons, minocycline prevents beta-amyloid-induced neuronal death, reduces caspase-3 activation, and lowers generation of caspase-3-cleaved tau fragments. Treatment of tangle-forming transgenic mice (htau line) with minocycline results in reduced levels of tau phosphorylation and insoluble tau aggregates. The in vivo effects of minocycline are also associated with reduced caspase-3 activation and lowered tau cleavage by caspase-3. In tau mice, we find that conformational changes in tau are susceptible to minocycline treatment, but are not directly associated with the amount of tau fragments produced, highlighting a dissociation between the development of these pathological tau species. These results suggest a possible novel therapeutic role for minocycline in the treatment of AD and related tauopathies.
阿尔茨海默病（AD）的特征是存在过度磷酸化、聚集的tau蛋白神经原纤维缠结以及β-淀粉样肽的细胞外沉积物。β-淀粉样蛋白水平升高被认为先于缠结形成，但tau病理与神经元死亡的关系更为密切。米诺环素是一种四环素衍生物，在几种神经退行性疾病模型中，包括具有淀粉样病理的AD模型中，具有强大的抗炎、抗凋亡和神经保护作用。我们使用了AD的体外和体内模型来确定米诺环素是否可能对tau病理具有治疗效果。在原代皮质神经元中，米诺环素可预防β-淀粉样蛋白诱导的神经元死亡，降低半胱天冬酶-3的激活，并减少半胱天冬酶-3切割的tau片段的产生。用米诺环素治疗形成缠结的转基因小鼠（htau品系）可降低tau磷酸化水平和不溶性tau聚集体。米诺环素的体内作用还与半胱天冬酶-3激活的减少和半胱天冬酶-3对tau切割的降低有关。在tau小鼠中，我们发现tau的构象变化对米诺环素治疗敏感，但与产生的tau片段数量没有直接关联，这突出了这些病理性tau物种发展之间的分离。这些结果表明米诺环素在治疗AD和相关tauopathies方面可能具有新的治疗作用。
