Trazodone modulates soluble ST2 levels, alleviates amyloid-beta pathology in APP/PS1 Alzheimer's mice

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder involving amyloidosis, immune dysfunctions, and synaptic impairments, all critical therapeutic targets. Repurposing existing drugs offers a cost-effective and faster development pathway. Genetic studies highlight the crucial role of microglial clearance of amyloid-beta (Aβ) in AD pathogenesis. Soluble ST2 (sST2), an isoform of the IL1RL1 gene, acts as a decoy receptor, interfering with IL-33/ST2 signaling and impairing microglial Aβ clearance functions, making its modulation a promising therapeutic strategy.

Researchers investigated drug repurposing opportunities to modulate sST2 levels and alleviate AD pathologies. They conducted an unbiased screening of commonly used medications in AD patients, followed by validation in model systems. This process identified trazodone—an antidepressant—as a leading negative regulator of sST2. The study then validated trazodone's effects in the APP/PS1 transgenic mouse model of AD. Key assessments included sST2 expression, microglial interaction with Aβ, Aβ pathology, neurodegeneration, synaptic deficits, and molecular profiling of synaptic proteins.

Trazodone was identified as a potent negative regulator of sST2 expression, primarily suppressing it through its antagonistic effects on adrenergic signaling. In the APP/PS1 transgenic mouse model of AD, trazodone treatment significantly enhanced microglial interaction with Aβ, leading to an alleviation of Aβ pathology. Furthermore, trazodone reduced markers of neurodegeneration and successfully rescued synaptic deficits in the treated APP/PS1 mice.

Comprehensive molecular profiling of APP/PS1 mouse brains showed that trazodone restored the expression of synaptic proteins critical for synaptic integrity and plasticity. These findings demonstrate trazodone's potential to target underlying immune dysfunctions and synaptic impairment in AD.