ICAM-1 mediated inhibition of microglial inflammation through ERK/STAT3 signalling pathway improves cognitive functions in 5xFAD mouse model of Alzheimer's disease.

Abstract

Microgliosis is one of the early hallmarks of Alzheimer's disease (AD) that plays a crucial role in disease pathogenesis. Microglia play a defensive role by phagocytosing and clearing amyloid-β (Aβ) aggregates. However, excessive uptake of Aβ leads to impairment of its clearing ability, which results in neuroinflammation and eventually neurodegeneration. Thus, enhancing microglial phagocytosis and reducing its pro-inflammatory functions are promising strategies for AD therapy. However, harnessing microglial activation for long-term benefits in controlling disease pathogenesis in AD is currently lacking. Our recent findings revealed that the astrocyte secreted cytokine Intercellular adhesion molecule 1 (ICAM-1) improves memory and cognitive impairments in a 5xFAD mouse model of AD. Here, we investigated the involvement of microglia in ICAM-1 function since its receptor, LFA-1, is expressed in microglia. We found that ICAM-1 blocks Aβ-mediated microglial inflammatory activation by inhibiting the ERK-STAT3 pathway, which is indispensable for microglial inflammation. Further, we found that ICAM-1 potentiates microglial phagocytic ability to eliminate Aβ in primary culture. Additionally, ICAM-1 reduced Aβ plaque load and associated microglial reactivation in the 5xFAD mouse hippocampus. This reduction in plaque-associated microgliosis led to improved synaptic protein expressions which was reflected in significant cognitive improvement. Moreover, blocking the binding between ICAM-1 with its receptor LFA-1 partially reduced ICAM-1-mediated microglial modification. Collectively, these findings suggest that ICAM-1 plays a pivotal role in modifying microglial phagocytic and inflammatory functions via the ERK-STAT3 signalling pathway, thereby contributing to Aβ clearance and cognitive improvements.