LRRK2 Kinase Inhibition Attenuates Neuroinflammation and Cytotoxicity in Animal Models of Alzheimer’s and Parkinson’s Disease-Related Neuroinflammation

Abstract

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 have started to be considered as a 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 Aβ1-42 fibrils or α-syn preformed 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.

The Role of Immune Dysfunction in Parkinson’s Disease Development

“…This inhibition effectively alleviates neuroinflammationinduced dopaminergic neuronal loss in various experimental models, including mouse glioma cells, primary rat microglia, and human microglia cell lines [42]. Furthermore, studies have demonstrated that LRRK2 kinase inhibition attenuates neuroinflammation, gliosis, and cytotoxicity in murine models receiving intracerebral injections of α-syn preformed fibrils, thereby reinforcing the anti-inflammatory potential of LRRK2 kinase inhibition in preclinical settings [43]. Recent investigations employing a chimeric mouse model revealed that replacing mutant LRRK2 with the wild-type variant of the protein in T-and B-lymphocytes exerts a marked reduction in lipopolysaccharide (LPS)-mediated inflammation [43].…”

“…Furthermore, studies have demonstrated that LRRK2 kinase inhibition attenuates neuroinflammation, gliosis, and cytotoxicity in murine models receiving intracerebral injections of α-syn preformed fibrils, thereby reinforcing the anti-inflammatory potential of LRRK2 kinase inhibition in preclinical settings [43]. Recent investigations employing a chimeric mouse model revealed that replacing mutant LRRK2 with the wild-type variant of the protein in T-and B-lymphocytes exerts a marked reduction in lipopolysaccharide (LPS)-mediated inflammation [43]. Additionally, this genetic alteration rescues dopaminergic neuron loss within the substantia nigra pars compacta, underscoring the profound influence of LRRK2 mutations on the adaptive immune system and its significant role in shaping neuropathological outcomes [44].…”

Analysis of MicroRNA-Transcription Factors Co-Regulatory Network Linking Depression and Vitamin D Deficiency

“…LRRK2, a major modulator of neuroinflammation involved in the pathogenesis of Parkinson's disease, is upregulated in both depressive (logFC = 0.56) and VDD (logFC = 2.57) patients [47,48]. LRRK2 mutations have been found in individuals without manifest Parkinson's disease, in which compensatory changes in the serotonergic system were described [49].…”

Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders

“…Overall, there is extensive evidence that LRRK2 kinase activity modulates PD-relevant neuroinflammatory responses [223][224][225]. Thus, the inhibition of LRRK2 kinase activity is an exciting experimental approach [225,226]. Given such promise, ongoing clinical trials are being conducted [227].…”