Phenylbutyrate is a Multifaceted Drug that Exerts Neuroprotective Effects and Reverses the Alzheimer's Disease-like Phenotype of a Commonly Used Mouse Model
Phenylbutyrate is a Multifaceted Drug that Exerts Neuroprotective Effects and Reverses the Alzheimer's Disease-like Phenotype of a Commonly Used Mouse Model
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DOI：
10.2174/1381612811319280006
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发表时间：
2013-08-01
影响因子：
3.1
通讯作者：
Garcia-Osta, Ana
中科院分区：
文献类型：
--
作者：
Cuadrado-Tejedor, Mar;Ricobaraza, Ana L.;Garcia-Osta, Ana
4-苯丁酸（PBA）是组蛋白脱乙酰酶（HDAC）抑制剂，其在阿尔茨海默病（AD）的Tg 2576小鼠模型中的功效与降低的tau磷酸化、神经元内A β的清除和海马CA 1锥体神经元中树突棘密度的恢复相关。PBA也是促进细胞蛋白质稳态的化学伴侣。为了确定HDAC抑制和伴侣样活性在PBA的抗AD作用中的相对贡献，我们比较了PBA与丁酸钠（NaBu）（一种无伴侣活性的HDAC抑制剂）的作用。在Tg 2576小鼠的神经元培养物中，我们观察到组蛋白3乙酰化与p-tau水平降低之间的相关性。此外，我们观察到的淀粉样前体蛋白（APP）的处理与PBA Tg 2576神经元中的减少，但不与NaBu。在给予PBA或NaBu 3周的Tg 2576小鼠中，只有PBA使病理性AD标志物正常化，这至少部分地暗示了Tg 2576小鼠AD样表型逆转中的伴侣样活性的其他机制。此外，用PBA而不是NaBu处理防止了hAPP（WT）过表达小鼠海马中的神经元损失，如在CA 1层中特别明显的。除了其作为HDAC抑制剂的活性之外，PBA的伴侣活性似乎至少部分地介导其在Tg 2576小鼠中的AD表型的逆转及其在海马神经元损失模型中的神经保护作用。
4-phenylbutyrate (PBA) is a histone deacetylase (HDAC) inhibitor whose efficacy in the Tg2576 mouse model of Alzheimer's disease (AD) is correlated with decreased tau phosphorylation, clearance of intraneuronal A beta and restoration of dendritic spine density in hippocampal CA1 pyramidal neurons. PBA is also a chemical chaperone that facilitates cell proteostasis. To determine the relative contributions of HDAC inhibition and chaperone-like activity in the anti-AD effects of PBA, we compared the effect of PBA with that of sodium butyrate (NaBu), an HDAC inhibitor with no chaperone activity. In neuronal cultures from Tg2576 mice, we observed a correlation between histone 3 acetylation and decreased p-tau levels. Moreover, we observed a decrease in the processing of the amyloid precursor protein (APP) in Tg2576 neurons treated with PBA, but not with NaBu. In Tg2576 mice administered PBA or NaBu for 3 weeks, only PBA normalized the pathological AD markers, implicating, at least in part, other mechanism as the chaperone-like activity in the reversal of the AD-like phenotype of Tg2576 mice. Furthermore, treatment with PBA but not NaBu prevented the neuronal loss in the hippocampus of hAPP(WT)-overexpressing mice, as was particularly evident in the CA1 layer. In addition to its activity as a HDAC inhibitor, the chaperone activity of PBA appears to at least partially, mediate its reversal of the AD phenotype in Tg2576 mice and its neuroprotective effect in a model of hippocampal neuronal loss.