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      Gutting the brain of inflammation: A key role of gut microbiome in human umbilical cord blood plasma therapy in Parkinson's disease model

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          Abstract

          Current therapies for Parkinson's disease (PD), including L‐3,4‐dihydroxyphenylalanine (L‐DOPA), and clinical trials investigating dopaminergic cell transplants, have generated mixed results with the eventual induction of dyskinetic side effects. Although human umbilical cord blood (hUCB) stem/progenitor cells present with no or minimal capacity of differentiation into mature dopaminergic neurons, their transplantation significantly attenuates parkinsonian symptoms likely via bystander effects, specifically stem cell graft‐mediated secretion of growth factors, anti‐inflammatory cytokines, or synaptic function altogether promoting brain repair. Recognizing this non‐cell replacement mechanism, we examined here the effects of intravenously transplanted combination of hUCB‐derived plasma into the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced rat model of PD. Animals received repeated dosing of either hUCB‐derived plasma or vehicle at 3, 5 and 10 days after induction into MPTP lesion, then behaviourally and immunohistochemically evaluated over 56 days post‐lesion. Compared to vehicle treatment, transplantation with hUCB‐derived plasma significantly improved motor function, gut motility and dopaminergic neuronal survival in the substantia nigra pars compacta (SNpc), which coincided with reduced pro‐inflammatory cytokines in both the SNpc and the intestinal mucosa and dampened inflammation‐associated gut microbiota. These novel data directly implicate a key pathological crosstalk between gut and brain ushering a new avenue of therapeutically targeting the gut microbiome with hUCB‐derived stem cells and plasma for PD.

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          Bidirectional switch of the valence associated with a hippocampal contextual memory engram

          Roger Redondo, Joshua Kim, Autumn L Arons … (2014)
          The valence of memories is malleable because of their intrinsic reconstructive property 1 . This property of memory has been used clinically to treat maladaptive behaviours 2 . However, the neuronal mechanisms and brain circuits that enable the switching of the valence of memories remain largely unknown. Here, we investigated these mechanisms by applying the recently developed memory engram cell-labelling and -manipulation technique 3,4 . We labelled, with Channelrhodopsin-2 (ChR2), a population of cells in either the dorsal dentate gyrus (DG) of the hippocampus or the basolateral complex of the amygdala (BLA) that were specifically activated during contextual fear or reward conditioning. Both groups of fear-conditioned mice displayed aversive light-dependent responses in an optogenetic place avoidance test, whereas both DG- and BLA-labelled mice that underwent reward conditioning exhibited an appetitive response in an optogenetic place preference test. Next, in an attempt to reverse the valence of memory within a subject, mice whose DG or BLA engram had initially been labelled by contextual fear or reward conditioning were subjected to a second conditioning of the opposite valence while their original DG or BLA engram was reactivated by blue light. Subsequent optogenetic place avoidance and preference tests revealed that while the DG-engram group displayed a response indicating a switch of the memory valence, the BLA-engram group did not. This switch was also evident at the cellular level by a change in functional connectivity between DG engram-bearing cells and BLA engram-bearing cells. Thus, we found that in the DG, the neurons carrying the memory engram of a given neutral context have plasticity such that the valence of a conditioned response evoked by their reactivation can be reversed by re-associating this contextual memory engram with a new US of an opposite valence. Our present work provides new insight into the functional neural circuit underlying the malleability of emotional memory.
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            A Role for Neuronal Alpha-Synuclein in Gastrointestinal Immunity

            Michael A. Zasloff, Denise Barbut, Brent E. Harris … (2017)
            Background Alpha-synuclein (αS) is a nerve cell protein associated with Parkinson disease (PD). Accumulation of αS within the enteric nervous system (ENS) and its traffic from the gut to the brain are implicated in the pathogenesis and progression of PD. αS has no known function in humans and the reason for its accumulation within the ENS is unknown. Several recent studies conducted in rodents have linked αS to immune cell activation in the central nervous system. We hypothesized that αS in the ENS might play a role in the innate immune defenses of the human gastrointestinal (GI) tract. Methods We immunostained endoscopic biopsies for αS from children with documented gastric and duodenal inflammation and intestinal allograft recipients who contracted norovirus. To determine whether αS exhibited immune-modulatory activity, we examined whether human αS induced leukocyte migration and dendritic cell maturation. Findings We showed that the expression of αS in the enteric neurites of the upper GI tract of pediatric patients positively correlated with the degree of acute and chronic inflammation in the intestinal wall. In intestinal allograft subjects who were closely monitored for infection, expression of αS was induced during norovirus infection. We also demonstrated that both monomeric and oligomeric αS have potent chemoattractant activity, causing the migration of neutrophils and monocytes dependent on the presence of the integrin subunit, CD11b, and that both forms of αS stimulate dendritic cell maturation. Interpretation These findings strongly suggest that αS is expressed within the human ENS to direct intestinal inflammation and implicates common GI infections in the pathogenesis of PD.
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              Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson's disease.

              Andrew D. A. C. Smith, Mark Hauser, Craig D. Perl … (1995)
              Trials are under way to determine whether fetal nigral grafts can improve motor function in patients with Parkinson's disease. Some studies use fluorodopa uptake on positron-emission tomography (PET) as a marker of graft viability, but fluorodopa uptake does not distinguish between host and grafted neurons. There has been no direct evidence that grafts of fetal tissue can survive and innervate the striatum. We studied a 59-year-old man with advanced Parkinson's disease who received bilateral grafts of fetal ventral mesencephalic tissue in the postcommissural putamen. The tissue came from seven embryos between 6 1/2 and 9 weeks after conception. The patient died 18 months later from a massive pulmonary embolism. The brain was studied with the use of tyrosine hydroxylase immunohistochemical methods. After transplantation, the patient had sustained improvement in motor function and a progressive increase in fluorodopa uptake in the putamen on PET scanning. On examination of the brain, each of the large grafts appeared to be viable. Each was integrated into the host striatum and contained dense clusters of dopaminergic neurons. Processes from these neurons had grown out of the grafts and provided extensive dopaminergic reinnervation to the striatum in a patch-matrix pattern. Ungrafted regions of the putamen showed sparse dopaminergic innervation. We could not identify any sprouting of host dopaminergic processes. Grafts of fetal mesencephalic tissue can survive for a long period in the human brain and restore dopaminergic innervation to the striatum in patients with Parkinson's disease. In the patient we studied, clinical improvement and enhanced fluorodopa with uptake on PET scanning were associated the survival of the grafts and dopaminergic reinnervation of the striatum.
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                Author and article information

                Contributors
                Cesario V. Borlongan:
                ORCID: https://orcid.org/0000-0002-2966-9782
                cborlong@health.usf.edu
                Journal
                Journal ID (nlm-ta): J Cell Mol Med
                Journal ID (iso-abbrev): J. Cell. Mol. Med
                Journal ID (doi): 10.1111/(ISSN)1582-4934
                Journal ID (publisher-id): JCMM
                Title: Journal of Cellular and Molecular Medicine
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 1582-1838
                ISSN (Electronic): 1582-4934
                Publication date (Electronic): 31 May 2019
                Publication date (Print): August 2019
                Volume: 23
                Issue: 8 ( doiID: 10.1111/jcmm.2019.23.issue-8 )
                Pages: 5466-5474
                Affiliations
                [ 1 ] Center of Excellence for Aging and Brain Repair Morsani College of Medicine, University of South Florida Tampa Florida
                [ 2 ] Department of Neurosurgery and Brain Repair Morsani College of Medicine, University of South Florida Tampa Florida
                [ 3 ] Saneron CCEL Therapeutics, Inc. Tampa Florida
                [ 4 ] Department of Pathology and Cell Biology Morsani College of Medicine, University of South Florida Tampa Florida
                [ 5 ] Department of Psychiatry Morsani College of Medicine, University of South Florida Tampa Florida
                Author notes
                [*] [* ] Correspondence

                Cesario V. Borlongan, MA, PhD, Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd. MDC 78, Tampa, FL 33612.

                Email: cborlong@ 123456health.usf.edu

                Author information
                https://orcid.org/0000-0002-2966-9782
                Article
                Publisher ID: JCMM14429
                DOI: 10.1111/jcmm.14429
                PMC ID: 6653272
                PubMed ID: 31148353
                SO-VID: 7985c5e3-fac8-466b-af35-81aa175ae0be
                Copyright © © 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 22 April 2019
                Date revision received : 09 May 2019
                Date accepted : 11 May 2019
                Page count
                Figures: 4, Tables: 0, Pages: 9, Words: 6274
                Funding
                Funded by: University of South Florida
                Funded by: Saneron CCEL Therapeutics, Inc
                Categories
                Subject: Original Article
                Subject: Original Articles
                Custom metadata
                source-schema-version-number 2.0
                component-id jcmm14429
                cover-date August 2019
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.6.2 mode:remove_FC converted:24.07.2019

                ScienceOpen disciplines: Molecular medicine
                Keywords: cord blood,gut microbiome,neurodegeneration,neuroinflammation,plasma
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: cord blood, gut microbiome, neurodegeneration, neuroinflammation, plasma

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