期刊
AGING CELL
卷 20, 期 1, 页码 -出版社
WILEY
DOI: 10.1111/acel.13286
关键词
5HT(2A)R; Alzheimer' s disease; desloratadine; microglia; neuroinflammation
资金
- National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China [2018ZX09711002]
- National Natural Science Foundation for Young Scientists of China [81703806]
- Postgraduate Research & Practice Innovation Program of Jiangsu Province [KYCX18_1600]
- Open Project Program of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica [JKLPSE201801]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
- Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine)
- Innovative Research Team of Six Talent Peaks Project in Jiangsu Province [TD-SWYY-013]
This study found that desloratadine (DLT) functions as a selective antagonist of 5HT(2A)R and can effectively improve pathology in APP/PS1 mice by promoting microglial A beta phagocytosis and degradation, repressing neuroinflammation, and activating glucocorticoid receptors. The research suggests that 5HT(2A)R antagonism could be a promising therapeutic strategy for Alzheimer's disease and highlights the potential of DLT in its treatment.
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. 5HT(2A) receptor (5HT(2A)R) is a subtype of 5HT(2) 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 5HT(2A)R and efficiently ameliorated pathology of APP/PS1 mice. The underlying mechanism has been intensively investigated by assay against APP/PS1 mice with selective 5HT(2A)R knockdown in the brain treated by adeno-associated virus (AAV)-ePHP-si-5HT(2A)R. DLT reduced amyloid plaque deposition by promoting microglial A beta phagocytosis and degradation, and ameliorated innate immune response by polarizing microglia to an anti-inflammatory phenotype. It stimulated autophagy process and repressed neuroinflammation through 5HT(2A)R/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 5HT(2A)R antagonism might be a promising therapeutic strategy for AD and highlighted the potential of DLT in the treatment of this disease.
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