LRRK2-Mediated Neuroinflammation Induces Neuronal Dysfunctions in a Parkinson’s and Alzheimer’s Disease Cellular Model

Chronic neuroinflammation plays a crucial role in the progression of neurodegenerative diseases (NDs), including Parkinson's disease (PD) and Alzheimer's disease (AD). Leucine-Rich Repeat Kinase 2 (LRRK2), a gene linked to familial and sporadic PD, has been positively associated with neuroinflammation in both in vitro and in vivo systems. These observations suggest that LRRK2 might actively contribute to neuronal damage and degeneration in NDs. Based on these premises, we explored the impact of LRRK2-mediated neuroinflammation on neurons in a PD- and AD-related context. We set up a cellular model composed of human induced pluripotent stem cell (hiPSC)-derived neurons (dopaminergic for PD and cholinergic for AD) exposed to inflamed glial medium [α-synuclein pre-formed fibrils (α-syn pffs) for PD and amyloid-β (Aβ)_1-42 fibrils for AD] for several days. To dissect the effect of neuroinflammation, and specifically, the role of LRRK2, on neuronal functions, we first performed transcriptome analysis, and then, we validated the results at functional levels. Interestingly, we found that LRRK2-dependent neuroinflammation contributes to neuronal dysfunctions and death in both ND contexts and that LRRK2 kinase inhibition prevents these detrimental effects. Overall, our results suggest that lowering neuroinflammation through LRRK2 pharmacological inhibition might limit the progression of NDs and thus be neuroprotective.