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Neuroinflammation – Part 1

March 16, 2011

.Copyright 2009 by Parkinsonsonline.org and blogged on  A Matter of Balance.  May be distributed freely for non-commercial use so long as credit is maintained.
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A team from St. Judes in Memphis led by Richard J. Smeyne, this week published a report entitled
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“Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration”
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available as full text at http://www.pnas.org/content/early/2009/08/07/0900096106
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It is my opinion that this represents a watershed in our understanding of Parkinson’s Disease and that it provides “real world” confirmation of the work of German researcher Helmut Braak as well as half a dozen others. Even more importantly, it clearly shows the role of activated microglia and the resulting inflammation in PD. These confirmations of long-held suspicions lead to a number of important implications on not only the origins and progression, but the day to day nature of PD and new approaches to symptom management.

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For several years Braak and others have worked on the delineation of a pathway identical to that shown by Smeyne. Using Lewy bodies as a “footprint” they followed the same route from stomach to SN.
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“Early sites of Lewy pathology are the olfactory bulb and enteric plexus of the stomach…” and “…a neurotropic pathogen that, after penetration of the epithelia lining, could enter axons of the Meissner’s plexus and, via transsynaptic transmission, reach the preganglionic parasympathetic motor neurones of the vagus nerve. This would allow retrograde transport into the medulla and, from here, into the pons and midbrain until the substantia nigra is reached and typical aspects of disease commence.” Braak 2007  [PMID: 17961138 ]

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Smeyne summarizes current thinking as follows:
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It has been hypothesized that viruses have an etiological role in the development of several neurodegenerative disorders including the two most common, Alzheimer’s and Parkinson’s diseases (7). Each of these disorders are characterized by neuronal loss, abnormal protein aggregations (proteinopathies), and activation of the microglia that act as the brain’s innate immune system (8). Parkinson’s disease (PD) is characterized by a loss of the pigmented cells located in the midbrain’s substantia nigra pars compacta (SNpc), although cell loss has also been described in the locus coeruleus (9), the dorsal motor nucleus of the vagus nerve (10), and throughout the autonomic nervous system (11). In addition to neuronal loss, primary PD is also defined by the presence of proteinaceous inclusion bodies called Lewy bodies. Lewy bodies were first described and linked to PD by Frederic Lewy (12), and subsequently these have been shown to consist of a number of proteins including aggregated alpha-synuclein (13).”

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After infecting mice with the influenza virus and tracking it from stomach to the brain, Smeyne noted:
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… we observe activation of microglia and alpha-synuclein phosphorylation and aggregation that persists long after resolution of the infection. We also observe a significant loss of dopaminergic neurons in the substantia nigra pars compacta 60 days after infection.

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…the offending agent may cause a long lasting immune response in the brain that persists many years after the insult has resolved… Smeyne et al, 2009:

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This study brings up multiple points. One is the demonstration of Braak’s hypothetical pathogen. That does not mean that this is the only one, there may be others. If so, then it may be more accurate to say that this study demonstrates that Braak’s proposed route does, indeed, exist and may be used by one or more pathogens.

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Still another interpretation is that the study confirms the long-suspected role of neuroinflammation and microglial activation in particular. It is this latter view that is most important – the singular effect of microglial activation resulting from multiple causes.

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