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Cited by 197Parkinson's Disease Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration MechanismsNuclear Receptors and Signaling

Lewy body-like alpha-synuclein inclusions trigger reactive microgliosis prior to nigral degeneration

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Duffy, Megan F., Collier, Timothy J., Patterson, Joseph R., Kemp, Christopher J., Luk, Kelvin C., Tansey, Malú G., Paumier, Katrina L., Kanaan, Nicholas M. +8 more·2018·Journal of Neuroinflammation
DOI 10.1186/s12974-018-1171-zPMC PMC5930695
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Abstract

BACKGROUND: Converging evidence suggests a role for microglia-mediated neuroinflammation in Parkinson's disease (PD). Animal models of PD can serve as a platform to investigate the role of neuroinflammation in degeneration in PD. However, due to features of the previously available PD models, interpretations of the role of neuroinflammation as a contributor to or a consequence of neurodegeneration have remained elusive. In the present study, we investigated the temporal relationship of neuroinflammation in a model of synucleinopathy following intrastriatal injection of pre-formed alpha-synuclein fibrils (α-syn PFFS). METHODS: Male Fischer 344 rats (N = 114) received unilateral intrastriatal injections of α-syn PFFs, PBS, or rat serum albumin with cohorts euthanized at monthly intervals up to 6 months. Quantification of dopamine neurons, total neurons, phosphorylated α-syn (pS129) aggregates, major histocompatibility complex-II (MHC-II) antigen-presenting microglia, and ionized calcium-binding adaptor molecule-1 (Iba-1) immunoreactive microglial soma size was performed in the substantia nigra. In addition, the cortex and striatum were also examined for the presence of pS129 aggregates and MHC-II antigen-presenting microglia to compare the temporal patterns of pSyn accumulation and reactive microgliosis. RESULTS: Intrastriatal injection of α-syn PFFs to rats resulted in widespread accumulation of phosphorylated α-syn inclusions in several areas that innervate the striatum followed by significant loss (~ 35%) of substantia nigra pars compacta dopamine neurons within 5-6 months. The peak magnitudes of α-syn inclusion formation, MHC-II expression, and reactive microglial morphology were all observed in the SN 2 months following injection and 3 months prior to nigral dopamine neuron loss. Surprisingly, MHC-II immunoreactivity in α-syn PFF injected rats was relatively limited during the later interval of degeneration. Moreover, we observed a significant correlation between substantia nigra pSyn inclusion load and number of microglia expressing MHC-II. In addition, we observed a similar relationship between α-syn inclusion load and number of microglia expressing MHC-II in cortical regions, but not in the striatum. CONCLUSIONS: Our results demonstrate that increases in microglia displaying a reactive morphology and MHC-II expression occur in the substantia nigra in close association with peak numbers of pSyn inclusions, months prior to nigral dopamine neuron degeneration, and suggest that reactive microglia may contribute to vulnerability of SNc neurons to degeneration. The rat α-syn PFF model provides an opportunity to examine the innate immune response to accumulation of pathological α-syn in the context of normal levels of endogenous α-syn and provides insight into the earliest neuroinflammatory events in PD.

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Authors
Duffy, M. F., Collier, T. J., Patterson, J. R., Kemp, C. J., Luk, K. C., Tansey, M. G., Paumier, K. L., Kanaan, N. M., Fischer, D. L., Polinski, N. K., Barth, O. L., Howe, J. W., Vaikath, N. N., Majbour, N. K., El-Agnaf, O. M. A., & Sortwell, C. E.
Affiliations
  • Michigan State University (US)
  • University of Pennsylvania (US)
  • Emory University (US)
  • Hamad bin Khalifa University (QA)
Corresponding author
Sortwell, Caryl E.
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2018-05-01
Volume
15
Issue
1
Pages
129-129
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-018-1171-z
PMC
PMC5930695
OpenAlex
W2806961398
Cited by
197
References
77
Citations by year
2026: 13 · 2025: 20 · 2024: 29 · 2023: 20 · 2022: 29 · 2021: 31 · 2020: 33 · 2019: 16 · 2018: 6
FWCI
14.60
Type
journal article
Language
en
Update notices
correction (2018-05-29)
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
National Institute of Neurological Disorders and Stroke (NS099416)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
Parkinson's disease, alpha-synuclein, reactive microgliosis, neuroinflammation, substantia nigra, dopamine neuron loss, MHC class II antigen presentation, synucleinopathies, striatum, Iba1, animal models
MeSH terms
Animals, Injections, Intraventricular, Male, Nerve Degeneration, Rats, Inbred F344, Substantia Nigra, Lewy Bodies, Microglia, Rats, alpha-Synuclein

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