Abstract
In addition to driving dependency and overdose, illicit use of opioids, such as fentanyl, is linked to the risk for cognitive decline and dementia. Growing evidence also indicates that opioid use is associated with pathological features, paralleled early in Alzheimer's disease (AD), which raises the possibility of the involvement of mechanistic interactions between opioid use and AD progression. Here, we investigate how chronic fentanyl use (i.e., 20 days) influences the neuroimmune state, microglial activity, and amyloid burden in wildtype and APPPS1-21 mice, a transgenic model of AD. In wild-type mice, fentanyl use promoted a pro-inflammatory state without increasing the incidence of disease-associated microglia. In APPPS1-21 mice, chronic fentanyl use led to a shift favoring an anti-inflammatory state, which was associated with increased microglia clustering and activation at Aβ plaques, increased Aβ internalization in plaque-associated activated microglia, decreased soluble Aβ, and decreased plaque burden. Our findings indicate that chronic fentanyl use fundamentally changes the trajectory of neuroimmune activity and features characteristic of early AD by enabling microglia to enhance Aβ clearance. The interactions demonstrate how substance use can reshape the neuroimmune landscape in neurodegenerative disease, emphasizing the importance of tailored treatment strategies.