Linking Neuroinflammation and Neurodegeneration in Parkinson's Disease

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Abstract

Neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD) impose a pressing burden on our developed and consequently aging society. Misfolded protein aggregates are a critical aspect of several neurodegenerative diseases. Nevertheless, several questions remain unanswered regarding the role of misfolded protein aggregates and the cause of neuronal cell death. Recently, it has been postulated that neuroinflammatory processes might play a crucial role in the pathogenesis of PD. Numerous postmortem, brain imaging, epidemiological, and animal studies have documented the involvement of the innate and adaptive immunity in neurodegeneration. Whether these inflammatory processes are directly involved in the etiology of PD or represent secondary consequences of nigrostriatal pathway injury is the subject of intensive research. Immune alterations in response to extracellular α-synuclein may play a critical role in modulating Parkinson's disease progression. In this review, we address the current concept of neuroinflammation and its involvement in PD-associated neurodegeneration.

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Most cited references 71

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Stages in the development of Parkinson's disease-related pathology.

Heiko Braak, Estifanos Ghebremedhin, Udo Rüb … (2004)

The synucleinopathy, idiopathic Parkinson's disease, is a multisystem disorder that involves only a few predisposed nerve cell types in specific regions of the human nervous system. The intracerebral formation of abnormal proteinaceous Lewy bodies and Lewy neurites begins at defined induction sites and advances in a topographically predictable sequence. As the disease progresses, components of the autonomic, limbic, and somatomotor systems become particularly badly damaged. During presymptomatic stages 1-2, inclusion body pathology is confined to the medulla oblongata/pontine tegmentum and olfactory bulb/anterior olfactory nucleus. In stages 3-4, the substantia nigra and other nuclear grays of the midbrain and forebrain become the focus of initially slight and, then, severe pathological changes. At this point, most individuals probably cross the threshold to the symptomatic phase of the illness. In the end-stages 5-6, the process enters the mature neocortex, and the disease manifests itself in all of its clinical dimensions.

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Doris Blum-Degena, Thomas Muller, Wilfried Kuhn … (1995)

Interleukin-1 beta (IL-1 beta), interleukin-2 (IL-2), and interleukin-6 (IL-6) were measured in the cerebrospinal fluid (CSF) and plasma of 12 control subjects, 11 sporadic Alzheimer's disease (AD) and 22 de novo Parkinson's disease (PD) patients using high sensitivity enzyme-linked immunosorbent assays (ELISA). IL-1 beta and IL-6 contents were significantly elevated in the CSF of de novo PD and AD patients in comparison to the control group. In contrast, the plasma levels were not significantly affected. IL-2 contents in the CSF and plasma samples were unchanged in the three groups compared. Because the two cytokines IL-1 beta and IL-6 are known to play a key role in the interaction between the nervous and immune system, e.g. in the so-called acute phase response, our results support the involvement of immunological events in the complex process of neurodegeneration in AD and PD.

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Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease.

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1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages the nigrostriatal dopaminergic pathway as seen in Parkinson's disease (PD), a common neurodegenerative disorder with no effective protective treatment. Consistent with a role of glial cells in PD neurodegeneration, here we show that minocycline, an approved tetracycline derivative that inhibits microglial activation independently of its antimicrobial properties, mitigates both the demise of nigrostriatal dopaminergic neurons and the formation of nitrotyrosine produced by MPTP. In addition, we show that minocycline not only prevents MPTP-induced activation of microglia but also the formation of mature interleukin-1beta and the activation of NADPH-oxidase and inducible nitric oxide synthase (iNOS), three key microglial-derived cytotoxic mediators. Previously, we demonstrated that ablation of iNOS attenuates MPTP-induced neurotoxicity. Now, we demonstrate that iNOS is not the only microglial-related culprit implicated in MPTP-induced toxicity because mutant iNOS-deficient mice treated with minocycline are more resistant to this neurotoxin than iNOS-deficient mice not treated with minocycline. This study demonstrates that microglial-related inflammatory events play a significant role in the MPTP neurotoxic process and suggests that minocycline may be a valuable neuroprotective agent for the treatment of PD.

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Author and article information

Contributors

Anke Van der Perren:

ORCID: http://orcid.org/0000-0003-2924-7392

Journal

Journal ID (nlm-ta): J Immunol Res

Journal ID (iso-abbrev): J Immunol Res

Journal ID (publisher-id): JIR

Title: Journal of Immunology Research

Publisher: Hindawi

ISSN (Print): 2314-8861

ISSN (Electronic): 2314-7156

Publication date Collection: 2018

Publication date (Electronic): 16 April 2018

Volume: 2018

Electronic Location Identifier: 4784268

Affiliations

Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Leuven, Belgium

Author notes

Academic Editor: Marcella Reale

Author information

Géraldine Gelders http://orcid.org/0000-0003-4471-0365

Anke Van der Perren http://orcid.org/0000-0003-2924-7392

Article

DOI: 10.1155/2018/4784268

PMC ID: 5926497

PubMed ID: 29850629

SO-VID: 62a25465-6929-489f-b89c-19325978ad32

License:

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 4 January 2018

Date accepted : 28 March 2018

Funding

Funded by: FWO Flanders

Funded by: KU Leuven

Funded by: ERA-NET JPco-fuND 2015 SYNACTION

Funded by: Queen Elisabeth Medical Foundation for Neurosciences

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