LRRK2 kinase inhibition attenuates neuroinflammation and cytotoxicity in animal models of Alzheimer's and Parkinson's disease-related neuroinflammation

Chronic neuroinflammation plays a crucial role in the progression of several neurodegenerative diseases (NDDs), including Parkinson's disease (PD) and Alzheimer's disease (AD). Intriguingly, in the last decade, Leucine-Rich Repeat Kinase-2 (LRRK2), a gene mutated in familial and sporadic PD, was revealed as a key mediator of neuroinflammation. Therefore, the anti-inflammatory properties of LRRK2 inhibitors are started to be considered as disease-modifying treatment for PD; however, to date, there is little evidence on the beneficial effects of targeting LRRK2-related neuroinflammation in preclinical models.

In this study, we further validated LRRK2 kinase modulation as a pharmacological intervention in preclinical models of AD- and PD-related neuroinflammation. Specifically, we reported that LRRK2 kinase inhibition with MLi2 and PF-06447475 (PF) molecules attenuated neuroinflammation, gliosis and cytotoxicity in mice with intracerebral injection of Ab_1-42 fibrils or a-syn pre-formed fibrils (pffs). Moreover, for the first time in vivo, we showed that LRRK2 kinase activity participates in AD-related neuroinflammation and therefore might contribute to AD pathogenesis.

Overall, our findings added evidence on the anti-inflammatory effects of LRRK2 kinase inhibition in preclinical models and indicate that targeting LRRK2 activity could be a disease-modifying treatment for NDDs with an inflammatory component.

This research was funded by the Italian Ministry of Health, Italy, Ricerca Finalizzata (Grant GR-2016-02362548; LRRK2 as a novel pharmacological target for treatment of neurodegenerative diseases).