Antiallergic drug desloratadine as a selective antagonist of 5HT_2A receptor ameliorates pathology of Alzheimer's disease model mice by improving microglial dysfunction

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_2AR) 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 5HT_2AR and efficiently ameliorated pathology of APP/PS1 mice. The underlying mechanism has been intensively investigated by assay against APP/PS1 mice with selective 5HT_2AR knockdown in the brain treated by adeno-associated virus (AAV)-ePHP-si-5HT_2AR. 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 5HT_2AR/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_2AR antagonism might be a promising therapeutic strategy for AD and highlighted the potential of DLT in the treatment of this disease.