Reductions in amyloid-beta-derived neuroinflammation, with minocycline, restore cognition but do not significantly affect tau hyperphosphorylation.
Reductions in amyloid-beta-derived neuroinflammation, with minocycline, restore cognition but do not significantly affect tau hyperphosphorylation.
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DOI：
10.3233/jad-2010-100204
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Green KN
中科院分区：
文献类型：
--
作者：
Parachikova A;Vasilevko V;Cribbs DH;LaFerla FM;Green KN
阿尔茨海默病（AD）的认知能力下降是病理性蛋白质积累和下游事件（包括升高和改变的炎症反应）的结果。炎症先前已与tau蛋白的异常磷酸化增加有关。为了确定内源性Aβ诱导的神经炎症是否在体内驱动tau磷酸化，我们用米诺环素（一种抗炎剂）治疗8个月大的3xTg-AD，以评估其如何影响认知下降和病理学发展。4-几个月的治疗使认知恢复到非转基因的表现。炎症分析显示GFAP、TNFα和IL 6显著降低，CXCL 1趋化因子KC和MIP 1a增加。米诺环素还降低了不溶性Aβ和可溶性原纤维的水平。尽管降低了tau激酶cdk 5共激活因子p25的水平，但米诺环素对tau病理学没有广泛的影响，只有一个磷酸化表位显示出治疗减少（S212/S214）。这些发现的总和表明，AD小鼠模型中炎症事件的减少可预防与病理学相关的认知缺陷，但内源性Aβ源性神经炎症对tau病理学的发展无显著贡献。
Cognitive decline in Alzheimer’s disease (AD) occurs as a result of the buildup of pathological proteins, and downstream events including an elevated and altered inflammatory response. Inflammation has previously been linked to increased abnormal phosphorylation of tau protein. To determine if endogenous Aβ-induced neuroinflammation drives tau phosphorylation in vivo we treated 8-month-old 3xTg-AD with minocycline, an anti-inflammatory agent, to assess how it influenced cognitive decline and development of pathology. 4-months of treatment restored cognition to non-transgenic performance. Inflammatory profiling revealed a marked decrease in GFAP, TNFα as well as IL6 and an increase in the CXCL1 chemokines KC and MIP1a. Minocycline also reduced levels of insoluble Aβ and soluble fibrils. Despite reducing levels of the tau kinase cdk5 coactivator p25, minocycline did not have wide effects on tau pathology with only one phospho-epitope showing reduction with treatment (S212/S214). The sum of these findings shows that reduction of the inflammatory events in an AD mouse model prevents cognitive deficits associated with pathology, but that endogenous Aβ-derived neuroinflammation does not contribute significantly to the development of tau pathology.