Antiallergic drug desloratadine as a selective antagonist of 5HT(2A) receptor ameliorates pathology of Alzheimer's disease model mice by improving microglial dysfunction.
Antiallergic drug desloratadine as a selective antagonist of 5HT(2A) receptor ameliorates pathology of Alzheimer's disease model mice by improving microglial dysfunction.
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抗过敏药物地氯雷他定作为 5HT(2A) 受体的选择性拮抗剂通过改善小胶质细胞功能障碍改善阿尔茨海默病模型小鼠的病理学
DOI：
10.1111/acel.13286
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发表时间：
2021-01
期刊：
影响因子：
7.8
通讯作者：
Shen X
中科院分区：
文献类型：
--
作者：
Lu J;Zhang C;Lv J;Zhu X;Jiang X;Lu W;Lu Y;Tang Z;Wang J;Shen X
阿尔茨海默病（Alzheimer's disease，AD）是一种进行性神经退行性疾病，以认知功能障碍、人格和行为改变为特征。到目前为止，还没有有效的治疗AD的方法。5-羟色胺2A受体（5 HT 2A receptor，5 HT 2AR）是5-羟色胺受体家族中5-HT 2受体的一个亚型，其拮抗剂已被临床用作抗精神病药物以缓解精神疾病。在这里，我们发现临床一线抗过敏药物地氯雷他定（DLT）作为5 HT 2AR的选择性拮抗剂，有效地改善APP/PS1小鼠的病理学。已经通过针对经腺相关病毒（AAV）-ePHP-si-5 HT 2AR处理的脑中具有选择性5 HT 2AR敲低的APP/PS1小鼠的测定深入研究了潜在机制。DLT通过促进小胶质细胞Aβ吞噬和降解减少淀粉样蛋白斑块沉积，并通过使小胶质细胞极化为抗炎表型来改善先天性免疫应答。它通过5-HT-2AR/cAMP/PKA/CREB/Sirt 1通路刺激自噬过程，抑制神经炎症反应，并激活糖皮质激素受体（GR）核转位，上调吞噬受体TLR 2和TLR 4的转录。总之，我们的工作高度支持5 HT 2AR拮抗可能是AD的一种有前途的治疗策略，并强调了DLT在治疗这种疾病中的潜力。DLT作为5 HT 2AR拮抗剂有效改善APP/PS1小鼠的认知障碍。简言之，DLT通过促进小胶质细胞Aβ吞噬和降解减少淀粉样斑块沉积，并通过抑制NF-κB易位改善免疫应答。它通过5-HT-2AR/cAMP/PKA/CREB/Sirt 1通路刺激自噬过程，抑制神经炎症反应;在小胶质细胞吞噬刺激下，激活GR核转位，上调TLR 2/4的表达。
Alzheimer's disease (AD) is a progressively neurodegenerative disease characterized by cognitive deficits and alteration of personality and behavior. As yet, there is no efficient treatment for AD. 5HT2A receptor (5HT2AR) is a subtype of 5HT2 receptor belonging to the serotonin receptor family, and its antagonists have been clinically used as antipsychotics to relieve psychopathy. Here, we discovered that clinically first‐line antiallergic drug desloratadine (DLT) functioned as a selective antagonist of 5HT2AR and efficiently ameliorated pathology of APP/PS1 mice. The underlying mechanism has been intensively investigated by assay against APP/PS1 mice with selective 5HT2AR knockdown in the brain treated by adeno‐associated virus (AAV)‐ePHP‐si‐5HT2AR. DLT reduced amyloid plaque deposition by promoting microglial Aβ phagocytosis and degradation, and ameliorated innate immune response by polarizing microglia to an anti‐inflammatory phenotype. It stimulated autophagy process and repressed neuroinflammation through 5HT2AR/cAMP/PKA/CREB/Sirt1 pathway, and activated glucocorticoid receptor (GR) nuclear translocation to upregulate the transcriptions of phagocytic receptors TLR2 and TLR4 in response to microglial phagocytosis stimulation. Together, our work has highly supported that 5HT2AR antagonism might be a promising therapeutic strategy for AD and highlighted the potential of DLT in the treatment of this disease. DLT as a 5HT2AR antagonist effectively improved cognitive impairment of APP/PS1 mice. Briefly, DLT reduced amyloid plaque deposition by promoting microglial Aβ phagocytosis and degradation, and ameliorated immune response by inhibiting translocation of NF‐κB. It stimulated autophagy process and repressed neuroinflammation through 5HT2AR/cAMP/PKA/CREB/Sirt1 pathway, and activated GR nuclear translocation to upregulate the expression of TLR2/4 in response to microglial phagocytosis stimulation.
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影响因子：
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作者：
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DOI：
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发表时间：
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影响因子：
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