LRRK2 kinase inhibition attenuates astrocytic activation in response to amyloid b1-42 fibrils

Background: Intracerebral accumulation of amyloid-b in the extracellular plaques of Alzheimer’s disease (AD) brains represents the main cause of reactive astrogliosis and neuroinflammatory response. Of relevance, Leucine-Rich-Repeat Kinase 2 (LRRK2), a kinase linked to genetic and sporadic Parkinson’s disease (PD), has been identified as a positive mediator of neuroinflammation upon different inflammatory stimuli, however its pathogenicity in AD remains mainly unexplored. Methods: In this study, by using pharmacological inhibition of LRRK2 and murine primary astrocytes, we explored whether LRRK2 regulates astrocytic activation in response to amyloid-b1-42 (Ab1-42) fibrils. Results: Our results show that primary astrocytes become activated and recruit LRRK2 upon Ab1-42 fibrils exposure. Moreover, we found that pharmacological inhibition of LRRK2, with two different kinase inhibitors, can attenuate Ab1-42-mediated inflammation and favor the clearance of Ab1-42 fibrils in astrocytes. Conclusions: Overall, our findings report that LRRK2 kinase activity modulates astrocytic reactivity and functions in the presence of Ab1-42 deposits and indicate that PD-linked LRRK2 might contribute to AD-related neuroinflammation and pathogenesis.