LRRK2 Kinase Inhibition Attenuates Astrocytic Activation in Response to Amyloid β1-42 Fibrils.

Abstract

Intracerebral accumulation of amyloid-β 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. In this study, by using pharmacological inhibition of LRRK2 and murine primary astrocytes, we explored whether LRRK2 regulates astrocytic activation in response to amyloid-β1-42 (Aβ1-42). Our results showed that murine primary astrocytes become reactive and recruit serine 935 phosphorylated LRRK2 upon Aβ1-42 fibril exposure. Moreover, we found that pharmacological inhibition of LRRK2, with two different kinase inhibitors, can attenuate Aβ1-42-mediated inflammation and favor the clearance of Aβ1-42 fibrils in astrocytes. Overall, our findings report that LRRK2 kinase activity modulates astrocytic reactivity and functions in the presence of Aβ1-42 deposits and indicate that PD-linked LRRK2 might contribute to AD-related neuroinflammation and pathogenesis.