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

• Type of Material: Article
• Authors: Megan F. Duffy, Michigan State University; Timothy J. Collier, Michigan State University; Joseph R. Patterson, Michigan State University; Christopher J. Kemp, Michigan State University; Kelvin C. Luk, University of Pennsylvania; Malu Tansey, Emory University; Katrina L. Paumier, Michigan State University; Nicholas M. Kanaan, Michigan State University; Luke D. Fischer, Michigan State University; Nicole K. Polinski, Michigan State University; Olivia L. Barth, Michigan State University; Jacob W. Howe, Michigan State University; Nishant N. Vaikath, Hamad Bin Khalifa University; Nour K. Majbour, Hamad Bin Khalifa University; Omar M. A. El-Agnaf, Hamad Bin Khalifa University; Caryl E. Sortwell, Michigan State University
• Language: English
• Date: 2018-05-01
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s12974-018-1171-z
• Title of Journal or Parent Work: Journal of Neuroinflammation
• ISSN: 1742-2094
• Volume: 15
• Start Page: 129
• End Page: 129
• Grant/Funding Information: A support was provided by the Department of Translational Science and Molecular Medicine, the Neuroscience Graduate Program, National Institute of Neurological Disorders and Stroke (NS099416), and the Edwin A. Brophy Endowment at Michigan State University.
• Keywords: MOUSE MODEL; PATHOLOGY; CEREBROSPINAL-FLUID; Immunology; RAT-BRAIN; Science & Technology; MOTOR IMPAIRMENT; Neurodegeneration; ALZHEIMERS-DISEASE; Major-histocompatibility complex-II; Animal models; ACTIVATION; Parkinson's disease; Microglia; TRANSGENIC MICE; SUBSTANTIA-NIGRA; Synucleinopathy; Selective vulnerability; PARKINSONS-DISEASE; Neurosciences; Neurosciences & Neurology; Life Sciences & Biomedicine; Neuroinflammation
• Research Categories: Biology, Neuroscience; Biology, Physiology

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.