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Single Inflammatory Trigger Leads to Neuroinflammation in LRRK2 Rodent Model without Degeneration of Dopaminergic Neurons

Schildt, A., Walker, M. D., Dinelle, K., Miao, Q., Schulzer, M., O'Kusky, J., Farrer, M. J., Doudet, D. J. & Sossi, V., 5-Feb-2019, In : Journal of Parkinson's Disease. 9, 1, p. 121-139 19 p.

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  • Single Inflammatory Trigger Leads to Neuroinflammation in LRRK2 Rodent Model without Degeneration of Dopaminergic Neurons

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DOI

  • Anna Schildt
  • Matthew D. Walker
  • Katherine Dinelle
  • Qing Miao
  • Michael Schulzer
  • John O'Kusky
  • Matthew J. Farrer
  • Doris J. Doudet
  • Vesna Sossi

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 [C-11]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 [C-11] 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.

Original languageEnglish
Pages (from-to)121-139
Number of pages19
JournalJournal of Parkinson's Disease
Volume9
Issue number1
Publication statusPublished - 5-Feb-2019

    Keywords

  • LPS, LRRK2 G2019S, neuroinflammation, Parkinson's disease, PET imaging, POSITRON-EMISSION-TOMOGRAPHY, IN-VIVO MEASUREMENT, MICROGLIAL ACTIVATION, PARKINSONS-DISEASE, SYSTEMIC INFLAMMATION, TRANSGENIC RATS, PET, DEFICITS, PERFORMANCE

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