The delta-opioid receptor: a therapeutic target for Alzheimer's disease

Alzheimer's disease (AD) presents a complex pathogenesis involving amyloid-β (Aβ) plaques, tau tangles, and neuroinflammation. Recent evidence highlights δ-opioid receptor (DOR) as a unique and promising therapeutic target for AD. This review summarizes current knowledge on DOR's multifaceted neuroprotective role in AD pathology. While its involvement in Aβ regulation appears context-dependent, DOR activation consistently attenuates tau hyperphosphorylation, modulates microglial dysfunction, suppresses harmful neuroinflammation and inhibits complement-mediated synaptic pruning. All these findings have been well documented in in vitro and in vivo AD animal models. Furthermore, preclinical findings from general depression and anxiety models indicate that selective DOR agonists could help alleviate neuropsychiatric symptoms like depression and agitation, which are commonly seen in AD. DOR-associated genetic markers have also shown AD diagnostic potential. We conclude that targeting DOR offers a novel and integrative strategy impacting key AD pathological hallmarks: Aβ, tau, and neuroinflammation, as well as managing cognitive and emotional symptoms. Future research should focus on elucidating precise molecular mechanisms and translating these findings into clinical applications for AD diagnosis and therapy.