Neuronally-directed effects of RXR activation in a mouse model of Alzheimer's disease.
Neuronally-directed effects of RXR activation in a mouse model of Alzheimer's disease.
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DOI：
10.1038/srep42270
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发表时间：
2017-02-16
影响因子：
4.6
通讯作者：
Landreth GE
中科院分区：
文献类型：
--
作者：
Mariani MM;Malm T;Lamb R;Jay TR;Neilson L;Casali B;Medarametla L;Landreth GE
阿尔茨海默病（AD）的特征在于广泛的神经元损失，伴随着记忆和认知的严重损害。我们研究了维甲酸X受体激动剂贝沙罗汀在AD侵袭性模型中的神经定向作用。我们报道了用贝沙罗汀治疗3.5个月大的5XFAD小鼠两周后，导致神经元内淀粉样沉积物的清除。重要的是，4月龄小鼠下托中的神经元损失减少了44%，8月龄小鼠皮质V层中的神经元损失减少了18%。此外，贝沙罗汀治疗改善了恐惧条件化小鼠的远程记忆稳定性，并改善了嗅觉交叉习惯化。神经元活力和功能的这些改善与突触后标志物PSD 95和突触前标志物突触素水平的显著增加相关。此外，贝沙罗汀预处理改善了体外原代5XFAD神经元对谷氨酸诱导的兴奋性毒性的反应。贝沙罗汀的有益作用伴随着减少斑块负荷、减少星形胶质细胞增生和抑制炎症基因表达。总的来说，这些数据提供了证据表明，贝沙罗汀治疗减少了神经元损失，提高了突触完整性标志物的水平，这与认知改善和AD的侵袭性模型有关。
Alzheimer’s disease (AD) is characterized by extensive neuron loss that accompanies profound impairments in memory and cognition. We examined the neuronally directed effects of the retinoid X receptor agonist bexarotene in an aggressive model of AD. We report that a two week treatment of 3.5 month old 5XFAD mice with bexarotene resulted in the clearance of intraneuronal amyloid deposits. Importantly, neuronal loss was attenuated by 44% in the subiculum in mice 4 months of age and 18% in layer V of the cortex in mice 8 months of age. Moreover, bexarotene treatment improved remote memory stabilization in fear conditioned mice and improved olfactory cross habituation. These improvements in neuron viability and function were correlated with significant increases in the levels of post-synaptic marker PSD95 and the pre-synaptic marker synaptophysin. Moreover, bexarotene pretreatment improved neuron survival in primary 5XFAD neurons in vitro in response to glutamate-induced excitotoxicity. The salutary effects of bexarotene were accompanied by reduced plaque burden, decreased astrogliosis, and suppression of inflammatory gene expression. Collectively, these data provide evidence that bexarotene treatment reduced neuron loss, elevated levels of markers of synaptic integrity that was linked to improved cognition and in an aggressive model of AD.