Repurposing Trazodone for Alzheimer's Disease to Modulate Soluble ST2 Levels and Alleviate Alzheimer's Pathology

Alzheimer’s disease (AD) is a multifactorial disorder involving various pathological mechanisms, such as amyloidosis, immune dysfunctions and synaptic impairments, which are important therapeutic targets. Repurposing drugs to target these mechanisms offers a promising approach to reduce the costs and duration of drug development. Notably, genetic studies underscore the role of microglial clearance of amyloid-beta (Aβ) in AD pathogenesis, with soluble ST2 (sST2) identified as a disease-modifying factor that impairs microglial clearance functions. In this study, we investigated drug repurposing opportunities to modulate sST2 levels and alleviate AD pathologies. Unbiased screening of common medications in AD patients and validation in model systems identified trazodone, an anti-depressant used to treat major depressive disorder, as a leading negative regulator of sST2. Trazodone primarily regulates sST2 expression through its antagonistic effects on adrenergic signaling. Importantly, trazodone treatment enhanced microglial interaction with Aβ and alleviated Aβ pathology in the APP/PS1 transgenic mouse model of AD. Furthermore, trazodone treatment reduced neurodegeneration and rescued synaptic deficits in APP/PS1 mice. Comprehensive molecular profiling of APP/PS1 mouse brains showed that trazodone restores the expression of synaptic proteins involved in synaptic integrity and plasticity. Collectively, these findings demonstrate that trazodone is a promising repurposing agent for AD that targets the underlying immune dysfunctions and synaptic deficits.