Microglial Deletion of <i>Hrh4</i> Alleviates Alzheimer's Disease Pathologies by Enhancing Microglial Phagocytosis of Amyloid‐β and Tau

Amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau) aggregation are hallmark pathogenic events in Alzheimer's disease (AD). Microglial clearance of these toxic aggregates is essential, yet the underlying mechanisms remain poorly understood. This study demonstrates that low-dose ionizing radiation (LDIR) provides protection against Aβ toxicity in vitro and rescues cognitive deficits in sporadic, young, and aged familial AD mouse models, including reductions in Aβ plaque, tauopathy, and microgliosis, while promoting microglial phagocytosis in aged 3xTg-AD mice. Transcriptomic analysis identifies VUF6002, a histamine H4 receptor (H₄R) antagonist, which mimics the beneficial effects of LDIR by promoting microglial activity. VUF6002 treatment restores cognitive function in aged 3xTg-AD and APPswe/PSEN1dE9 mice and significantly increases Aβ and p-tau clearance by resident microglia. Mechanistically, deletion of Hrh4 in microglia, but not in neurons, reverses cognitive deficits and mitigates key AD pathogenesis by activating the cAMP/TGF-β1/Smad3 pathway. These beneficial effects are completely abolished by inhibition of TGF-β receptor 1 signaling, which is also downregulated in AD patients. Collectively, these findings reveal a H₄R/cAMP/TGF-β1/Smad3 signaling axis involved in microglial phagocytosis and cognitive function, serving as a novel therapeutic target for AD.