Delta-Opioid Receptor Activation Confers both Microglia-Dependent and -Independent Neuroprotection against Alzheimer's Disease pathology

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaques, tau pathology, and neuroinflammation, with microglia playing a pivotal yet complex role. Although delta-opioid receptor (DOR) activation has demonstrated therapeutic potential in AD, its mechanisms remain incompletely understood. In this study, using 9-month-old 3xTg-AD mice, we found that DOR activation with UFP-512 reduced soluble Aβ, plaque load, phosphorylated tau, astrocyte activation, neuroinflammatory responses, and neuronal apoptosis, while also improving synaptic integrity and cognitive function. Depletion of microglia with PLX5622, a potent and selective agent of microglial depletion, abolished the beneficial effects of DOR activation on plaques, tau pathology, and synaptic protection, and attenuated its anti-inflammatory effects. Conversely, UFP-512 still lowered soluble Aβ, suppressed inflammatory astrocyte activation, and downregulated complement proteins C1q and C3 in the absence of microglia. Notably, microglial depletion prevented UFP-512 from providing further cognitive improvement. These results indicate that the therapeutic efficacy of DOR activation relies critically on microglial regulation, but also involves microglia-independent modulation of soluble Aβ, astrocyte reactivity, and complement expression, highlighting DOR agonism as a multimodal strategy that coordinates intercellular communication to ameliorate AD pathology.