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Single Inflammatory Trigger Leads to Neuroinflammation in LRRK2 Rodent Model without Degeneration of Dopaminergic
Anna Schildt1,2, Matthew D Walker1, Katherine Dinelle3
1Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada.
Background:
Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic risk factor for Parkinson's disease (PD). While the corresponding pathogenic mechanisms remain largely unknown, LRRK2 has been implicated in the immune system.
Objective:
To assess whether LRRK2 mutations alter the sensitivity to a single peripheral inflammatory trigger, with ultimate impact on dopaminergic integrity, using a longitudinal imaging-based study design.
Methods:
Rats carrying LRRK2 p.G2019S and non-transgenic (NT) littermates were treated peripherally with lipopolysaccharide (LPS). They were monitored over 10 months with PET markers for neuroinflammation and dopaminergic integrity, and with behavioral testing. Tyrosine hydroxylase and CD68 expression were assessed postmortem, 12 months after LPS treatment, in the striatum and substantia nigra.
Results:
Longitudinal [11C]PBR28 PET imaging revealed that LPS treatment caused inflammation in the brain, increasing over time, as compared to saline (corrected p = 0.008). LPS treated LRRK2 animals exhibited significantly increased neuroinflammation in the cortex and ventral-regions compared to saline treated animals (LRRK2 and NT) at 10 months post treatment, with the increase in [11C]PBR28 binding from baseline averaging 0.128±0.045 g/mL. For LPS treated NT animals, the increase was not significant. CD68 immunohistochemistry data supported the imaging results, but without reaching statistical significance. No dopaminergic degeneration was observed.
Conclusion:
A single peripheral inflammatory trigger elicited long lasting, progressive neuroinflammation. A trend for an exacerbated inflammatory response in LRRK2 animals compared to NT controls was observed. Translationally, this implies that repeated exposure to inflammatory triggers may be needed for LRRK2 mutation carriers to develop active PD.
Insights
Leucine-rich repeat kinase 2 (LRRK2) mutations may increase susceptibility to neuroinflammation following a single peripheral inflammatory event. This suggests repeated inflammation could be necessary for Parkinson's disease development in LRRK2 mutation carriers.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Leucine-rich repeat kinase 2 (LRRK2) mutations are a leading genetic risk factor for Parkinson's disease (PD).
- The precise mechanisms linking LRRK2 to PD pathogenesis are unclear, but LRRK2's role in immune system regulation is increasingly recognized.
Purpose of the Study:
- To investigate if LRRK2 mutations influence the brain's response to a peripheral inflammatory trigger.
- To assess the long-term impact on dopaminergic integrity and neuroinflammation using longitudinal imaging.
Main Methods:
- Rats with LRRK2 p.G2019S mutation and wild-type littermates received peripheral lipopolysaccharide (LPS) or saline.
- Longitudinal PET imaging ([11C]PBR28) monitored neuroinflammation and dopaminergic function over 10 months.
- Behavioral tests and postmortem analysis of tyrosine hydroxylase and CD68 expression were performed.
Main Results:
- LPS induced progressive neuroinflammation in the brain, evident on PET scans.
- LRRK2 mutant rats showed a trend towards exacerbated neuroinflammation compared to controls 10 months post-LPS.
- No significant dopaminergic degeneration was detected in any group.
Conclusions:
- A single peripheral inflammatory insult can cause sustained neuroinflammation.
- LRRK2 mutations may heighten susceptibility to inflammatory insults, potentially contributing to PD.
- Repeated inflammatory exposures might be critical for LRRK2 mutation carriers to develop active Parkinson's disease.
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