Academic Journal
View in EDS
Linked Full Text

Lack of neuroprotection after systemic administration of the soluble TNF inhibitor XPro1595 in an rAAV6-α-Syn + PFFs-induced rat model for Parkinson's disease

Bibliographic Details
Title: Lack of neuroprotection after systemic administration of the soluble TNF inhibitor XPro1595 in an rAAV6-α-Syn + PFFs-induced rat model for Parkinson's disease
Authors: Filip Fredlund, Claes Fryklund, Olivia Trujeque-Ramos, Hannah A. Staley, Joaquin Pardo, Kelvin C. Luk, Malú G. Tansey, Maria Swanberg
Source: Neurobiology of Disease, Vol 207, Iss , Pp 106841- (2025)
Publisher Information: Elsevier, 2025.
Publication Year: 2025
Collection: LCC:Neurosciences. Biological psychiatry. Neuropsychiatry
Subject Terms: TNF, Parkinson's disease, Neurodegeneration, Neuroinflammation, α-Synuclein, PFF, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
More Details: Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration, α-Synuclein (α-Syn) pathology, and inflammation. Microglia in the substantia nigra pars compacta (SNpc) upregulate major histocompatibility complex class II (MHCII), and variants in genes encoding MHCII affect PD risk. Additionally, elevated TNF levels and α-Syn-reactive T cells in circulation suggest a strong link between innate and adaptive immune responses in PD. We have previously reported that reduced levels of the class II transactivator, the master regulator of MHCII expression, increases susceptibility to α-Syn-induced PD-like pathology in rats and are associated with higher serum levels of soluble TNF (sTNF). Here, we demonstrate that inhibiting sTNF with a dominant-negative TNF variant, XPro1595, known to be neuroprotective in endotoxin- and toxin-induced neurodegeneration models, fails to protect against robust α-Syn-induced PD-like pathology in rats. We used a model combining rAAV-mediated α-Syn overexpression in SNpc with striatal injection of α-Syn preformed fibrils two weeks later. Systemic XPro1595 treatment was initiated one-week post-rAAV-α-Syn. We observed up to 70 % loss of striatal dopaminergic fibers without treatment, and no protective effects on dopaminergic neurodegeneration after XPro1595 administration. Pathological α-Syn levels as well as microglial and astrocytic activation were not reduced in SNpc or striatum following XPro1595 treatment. An increase in IL-6 and IL-1β levels in CSF was observed in rats treated with XPro1595, possibly explaining a lack of protective effects following treatment. Our results highlight the need to determine the importance of timing of treatment initiation, which is crucial for future applications of sTNF therapies in PD patients.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 1095-953X
Relation: http://www.sciencedirect.com/science/article/pii/S0969996125000579; https://doaj.org/toc/1095-953X
DOI: 10.1016/j.nbd.2025.106841
Access URL: https://doaj.org/article/f20c8e30213f458cba955dc06999d567
Accession Number: edsdoj.f20c8e30213f458cba955dc06999d567
Database: Directory of Open Access Journals
FullText Links:
  – Type: other
    Url: https://resolver.ebsco.com:443/public/rma-ftfapi/ejs/direct?AccessToken=4B04B41F475B266840A2&Show=Object
Text:
  Availability: 0
CustomLinks:
  – Url: https://www.doi.org/10.1016/j.nbd.2025.106841?
    Name: ScienceDirect (all content)-s8985755
    Category: fullText
    Text: View record from ScienceDirect
    MouseOverText: View record from ScienceDirect
  – Url: https://resolver.ebsco.com/c/xy5jbn/result?sid=EBSCO:edsdoj&genre=article&issn=1095953X&ISBN=&volume=207&issue=106841-&date=20250401&spage=&pages=&title=Neurobiology of Disease&atitle=Lack%20of%20neuroprotection%20after%20systemic%20administration%20of%20the%20soluble%20TNF%20inhibitor%20XPro1595%20in%20an%20rAAV6-%CE%B1-Syn%20%2B%20PFFs-induced%20rat%20model%20for%20Parkinson%27s%20disease&aulast=Filip%20Fredlund&id=DOI:10.1016/j.nbd.2025.106841
    Name: Full Text Finder (for New FTF UI) (s8985755)
    Category: fullText
    Text: Find It @ SCU Libraries
    MouseOverText: Find It @ SCU Libraries
  – Url: https://doaj.org/article/f20c8e30213f458cba955dc06999d567
    Name: EDS - DOAJ (s8985755)
    Category: fullText
    Text: View record from DOAJ
    MouseOverText: View record from DOAJ
Header DbId: edsdoj
DbLabel: Directory of Open Access Journals
An: edsdoj.f20c8e30213f458cba955dc06999d567
RelevancyScore: 1057
AccessLevel: 3
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 1056.58959960938
IllustrationInfo
Items – Name: Title
  Label: Title
  Group: Ti
  Data: Lack of neuroprotection after systemic administration of the soluble TNF inhibitor XPro1595 in an rAAV6-α-Syn + PFFs-induced rat model for Parkinson's disease
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AR" term="%22Filip+Fredlund%22">Filip Fredlund</searchLink><br /><searchLink fieldCode="AR" term="%22Claes+Fryklund%22">Claes Fryklund</searchLink><br /><searchLink fieldCode="AR" term="%22Olivia+Trujeque-Ramos%22">Olivia Trujeque-Ramos</searchLink><br /><searchLink fieldCode="AR" term="%22Hannah+A%2E+Staley%22">Hannah A. Staley</searchLink><br /><searchLink fieldCode="AR" term="%22Joaquin+Pardo%22">Joaquin Pardo</searchLink><br /><searchLink fieldCode="AR" term="%22Kelvin+C%2E+Luk%22">Kelvin C. Luk</searchLink><br /><searchLink fieldCode="AR" term="%22Malú+G%2E+Tansey%22">Malú G. Tansey</searchLink><br /><searchLink fieldCode="AR" term="%22Maria+Swanberg%22">Maria Swanberg</searchLink>
– Name: TitleSource
  Label: Source
  Group: Src
  Data: Neurobiology of Disease, Vol 207, Iss , Pp 106841- (2025)
– Name: Publisher
  Label: Publisher Information
  Group: PubInfo
  Data: Elsevier, 2025.
– Name: DatePubCY
  Label: Publication Year
  Group: Date
  Data: 2025
– Name: Subset
  Label: Collection
  Group: HoldingsInfo
  Data: LCC:Neurosciences. Biological psychiatry. Neuropsychiatry
– Name: Subject
  Label: Subject Terms
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22TNF%22">TNF</searchLink><br /><searchLink fieldCode="DE" term="%22Parkinson's+disease%22">Parkinson's disease</searchLink><br /><searchLink fieldCode="DE" term="%22Neurodegeneration%22">Neurodegeneration</searchLink><br /><searchLink fieldCode="DE" term="%22Neuroinflammation%22">Neuroinflammation</searchLink><br /><searchLink fieldCode="DE" term="%22α-Synuclein%22">α-Synuclein</searchLink><br /><searchLink fieldCode="DE" term="%22PFF%22">PFF</searchLink><br /><searchLink fieldCode="DE" term="%22Neurosciences%2E+Biological+psychiatry%2E+Neuropsychiatry%22">Neurosciences. Biological psychiatry. Neuropsychiatry</searchLink><br /><searchLink fieldCode="DE" term="%22RC321-571%22">RC321-571</searchLink>
– Name: Abstract
  Label: Description
  Group: Ab
  Data: Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration, α-Synuclein (α-Syn) pathology, and inflammation. Microglia in the substantia nigra pars compacta (SNpc) upregulate major histocompatibility complex class II (MHCII), and variants in genes encoding MHCII affect PD risk. Additionally, elevated TNF levels and α-Syn-reactive T cells in circulation suggest a strong link between innate and adaptive immune responses in PD. We have previously reported that reduced levels of the class II transactivator, the master regulator of MHCII expression, increases susceptibility to α-Syn-induced PD-like pathology in rats and are associated with higher serum levels of soluble TNF (sTNF). Here, we demonstrate that inhibiting sTNF with a dominant-negative TNF variant, XPro1595, known to be neuroprotective in endotoxin- and toxin-induced neurodegeneration models, fails to protect against robust α-Syn-induced PD-like pathology in rats. We used a model combining rAAV-mediated α-Syn overexpression in SNpc with striatal injection of α-Syn preformed fibrils two weeks later. Systemic XPro1595 treatment was initiated one-week post-rAAV-α-Syn. We observed up to 70 % loss of striatal dopaminergic fibers without treatment, and no protective effects on dopaminergic neurodegeneration after XPro1595 administration. Pathological α-Syn levels as well as microglial and astrocytic activation were not reduced in SNpc or striatum following XPro1595 treatment. An increase in IL-6 and IL-1β levels in CSF was observed in rats treated with XPro1595, possibly explaining a lack of protective effects following treatment. Our results highlight the need to determine the importance of timing of treatment initiation, which is crucial for future applications of sTNF therapies in PD patients.
– Name: TypeDocument
  Label: Document Type
  Group: TypDoc
  Data: article
– Name: Format
  Label: File Description
  Group: SrcInfo
  Data: electronic resource
– Name: Language
  Label: Language
  Group: Lang
  Data: English
– Name: ISSN
  Label: ISSN
  Group: ISSN
  Data: 1095-953X
– Name: NoteTitleSource
  Label: Relation
  Group: SrcInfo
  Data: http://www.sciencedirect.com/science/article/pii/S0969996125000579; https://doaj.org/toc/1095-953X
– Name: DOI
  Label: DOI
  Group: ID
  Data: 10.1016/j.nbd.2025.106841
– Name: URL
  Label: Access URL
  Group: URL
  Data: <link linkTarget="URL" linkTerm="https://doaj.org/article/f20c8e30213f458cba955dc06999d567" linkWindow="_blank">https://doaj.org/article/f20c8e30213f458cba955dc06999d567</link>
– Name: AN
  Label: Accession Number
  Group: ID
  Data: edsdoj.f20c8e30213f458cba955dc06999d567
PLink https://login.libproxy.scu.edu/login?url=https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&scope=site&db=edsdoj&AN=edsdoj.f20c8e30213f458cba955dc06999d567
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1016/j.nbd.2025.106841
    Languages:
      – Text: English
    Subjects:
      – SubjectFull: TNF
        Type: general
      – SubjectFull: Parkinson's disease
        Type: general
      – SubjectFull: Neurodegeneration
        Type: general
      – SubjectFull: Neuroinflammation
        Type: general
      – SubjectFull: α-Synuclein
        Type: general
      – SubjectFull: PFF
        Type: general
      – SubjectFull: Neurosciences. Biological psychiatry. Neuropsychiatry
        Type: general
      – SubjectFull: RC321-571
        Type: general
    Titles:
      – TitleFull: Lack of neuroprotection after systemic administration of the soluble TNF inhibitor XPro1595 in an rAAV6-α-Syn + PFFs-induced rat model for Parkinson's disease
        Type: main
  BibRelationships:
    HasContributorRelationships:
      – PersonEntity:
          Name:
            NameFull: Filip Fredlund
      – PersonEntity:
          Name:
            NameFull: Claes Fryklund
      – PersonEntity:
          Name:
            NameFull: Olivia Trujeque-Ramos
      – PersonEntity:
          Name:
            NameFull: Hannah A. Staley
      – PersonEntity:
          Name:
            NameFull: Joaquin Pardo
      – PersonEntity:
          Name:
            NameFull: Kelvin C. Luk
      – PersonEntity:
          Name:
            NameFull: Malú G. Tansey
      – PersonEntity:
          Name:
            NameFull: Maria Swanberg
    IsPartOfRelationships:
      – BibEntity:
          Dates:
            – D: 01
              M: 04
              Type: published
              Y: 2025
          Identifiers:
            – Type: issn-print
              Value: 1095953X
          Numbering:
            – Type: volume
              Value: 207
            – Type: issue
              Value: 106841-
          Titles:
            – TitleFull: Neurobiology of Disease
              Type: main
ResultId 1