miR-155 expression modulates microglia functions in vitro and in the APP/PS1 mouse model of Alzheimer’s disease

Abstract

Alzheimer’s Disease (AD) is characterized by the accumulation of extracellular Amyloid-β (Aβ) as well as both CNS and systemic inflammation. Microglia, myeloid cells resident to the CNS, use microRNAs to rapidly respond to inflammatory signals. MicroRNA (miRNA) profiles are altered in the tissue, circulating monocytes, and serum of AD patients. MiR-155 is a specific miRNA that modulates the phasic inflammatory responses of innate immune cells, however its precise role in AD pathogenesis remains unknown. We hypothesized that miR-155 participates in AD pathophysiology by regulating microglia responses to Aβ in vitro and in vivo. In cultured neonatal microglia, we observed that modulation of miR-155 expression impacts the internalization of fibrillar Aβ at the plasma membrane and to low-pH compartments. In mouse models of AD, microglia specific knock-out of miR-155 decreased accumulation of Aβ. In addition, we also observed that microglia specific deletion of miR-155 acutely increased seizures and seizure-related mortality in two mouse models of AD. Reduced Aβ plaques after miR-155 deletion in microglia suggests increased clearance and the hypothesis that in AD models, microglia facilitate epileptogenesis by increased internalization of synaptic material along with removal of Aβ. Together, these findings identify miR-155 expression in microglia as a potential regulator of synaptic homeostasis and microglia responses to Aβ in mouse models of AD.