Repurposing trazodone for Alzheimer's disease to modulate soluble ST2 levels and alleviate Alzheimer's pathology.

July 21, 2026| Source: Proceedings of the National Academy of Sciences of the United States of America

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. Genetic studies underscore the critical role of microglial clearance of amyloid-beta (Aβ) in AD pathogenesis. Specifically, soluble ST2 (sST2)-one of the two major isoforms of the ST2 protein encoded by the IL1RL1 (interleukin-1 receptor-like 1) gene-acts as a decoy receptor isoform that interferes with IL-33/ST2 signaling and has been identified as a disease-modifying factor that impairs microglial Aβ clearance functions. In this study, we investigated drug repurposing opportunities to modulate sST2 levels and alleviate AD pathologies. Unbiased screening of commonly used medications in AD patients, followed by validation in model systems, identified trazodone-an antidepressant used to treat major depressive disorder-as a leading negative regulator of sST2. Trazodone primarily suppresses sST2 expression through its antagonistic effects on adrenergic signaling. In the APP/PS1 transgenic mouse model of AD, trazodone treatment enhanced microglial interaction with Aβ and alleviated Aβ pathology. Furthermore, trazodone reduced neurodegeneration and rescued synaptic deficits in 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. Overall, these findings demonstrate that trazodone is a promising repurposing candidate for AD that targets underlying immune dysfunctions and synaptic impairment.

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Nature's antivenom: Combinations of conserved rattlesnake serum metalloproteinase inhibitors block the lethal action of viper venoms.

Snakebite maims or kills several hundred thousand people each year. For more than a century, treatment has relied on antivenoms derived from animals immunized with whole venoms, but their efficacy, safety, and availability are highly variable, and it is often not well understood which specific venom components must be inhibited to prevent mortality and major morbidities. New therapeutic approaches are needed. Here, we take an evolutionary approach to antivenom design inspired by the longstanding

Physical/TechAugust 4, 2026

Abrupt transition to irreversible damage in the overdrafted Sacramento Valley aquifer system.

Groundwater extraction decreases water pressure in aquifer systems, causing reversible or irreversible deformation of the water-bearing layers that manifests as recoverable or permanent displacements of the land surface, respectively. Detecting and forecasting when and where an aquifer system transitions from a reversible, poroelastic regime, to an irreversible, inelastic regime remains a crucial challenge given the complex, heterogeneous nature of aquifer systems. Here we leverage high-resoluti

Physical/TechJuly 28, 2026

Synergistic action of different molecular mechanisms causes striking levels of insecticide resistance in the malaria vector Anopheles gambiae .

Intensifying insecticide resistance in the malaria vector Anopheles gambiae poses a serious threat to the progress achieved the last decades in reducing malaria deaths in Africa. The genetic basis of insecticide resistance is often complex, involving multiple genes and mutations. However, we still lack a clear understanding of how each mechanism contributes to overall resistance and how highly resistant phenotypes arise. In this study, we generated a suite of transgenic An. gambiae strains carry

Physical/TechJuly 28, 2026

There is no free benchmark: An institutional view of legal AI benchmarking.

Despite substantial excitement around the use of AI in law, little information exists on the performance and associated risks of the domain's widely marketed tools. Recent work, for instance, has demonstrated the significant potential for "hallucinations"-wherein models make up facts, law, and precedent-leading Chief Justice Roberts to spotlight this risk in his annual report on the judiciary. We argue that there is a need for public AI benchmarking in law. First, relative to other AI applicatio

Physical/TechJuly 28, 2026

A phosphorylation cascade involving ZmSnRK2.10-ZmRIPK2-ZmWRKY38 attenuates drought response by derepressing ZmSUS2 in maize.

Drought stress severely limits crop productivity, with transcription factors (TFs) playing pivotal roles in plant adaptation. Here, we identify the maize TF ZmWRKY38 as a positive regulator of drought tolerance. CRISPR/Cas9-mediated knockout of ZmWRKY38 increased plant sensitivity to drought compared with the wild type. We demonstrate that ZmWRKY38 binds to the promoter of the sucrose synthase gene ZmSUS2 and represses its transcription. Conversely, ZmSUS2 functions as a negative regulator of dr