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Peripherally administered TNF inhibitor is not protective against α-synuclein-induced dopaminergic neuronal death in rats

Christiansen, Josefine R ; Ferreira, Sara A ; Szymkowski, David E ; Jakobsson, Johan LU orcid ; Tansey, Malú Gámez and Romero-Ramos, Marina LU (2025) In Neurobiology of Disease
Abstract

The underlying cause of neuronal loss in Parkinson's disease (PD) remains unknown, but evidence implicates neuroinflammation in PD pathobiology. The pro-inflammatory cytokine soluble tumor necrosis factor (TNF) seems to play an important role and thus has been proposed as a therapeutic target for modulation of the neuroinflammatory processes in PD. In this regard, dominant-negative TNF (DN-TNF) agents are promising antagonists that selectively inhibit soluble TNF signaling, while preserving the beneficial effects of transmembrane TNF. Previous studies have tested the protective potential of DN-TNF-based therapy in toxin-based PD models. Here we test for the first time the protective potential of a DN-TNF therapeutic against... (More)

The underlying cause of neuronal loss in Parkinson's disease (PD) remains unknown, but evidence implicates neuroinflammation in PD pathobiology. The pro-inflammatory cytokine soluble tumor necrosis factor (TNF) seems to play an important role and thus has been proposed as a therapeutic target for modulation of the neuroinflammatory processes in PD. In this regard, dominant-negative TNF (DN-TNF) agents are promising antagonists that selectively inhibit soluble TNF signaling, while preserving the beneficial effects of transmembrane TNF. Previous studies have tested the protective potential of DN-TNF-based therapy in toxin-based PD models. Here we test for the first time the protective potential of a DN-TNF therapeutic against α-synuclein-driven neurodegeneration in the viral vector-based PD female rat model. To do so, we administered the DN-TNF agent XPro1595 subcutaneously for a period of 12 weeks. In contrast to previous studies using different PD models, neuroprotection was not achieved by systemic XPro1595 treatment. α-synuclein-induced loss of nigrostriatal neurons, accumulation of pathological inclusions and microgliosis was detected in both XPro1595- and saline-treated animals. XPro1595 treatment increased the percentage of the hypertrophic/ameboid Iba1+ cells in SN and reduced the striatal MHCII+ expression in the α-synuclein-overexpressing animals. However, the treatment did not prevent the MHCII upregulation seen in the SN of the model, nor the increase of CD68+ phagocytic cells. Therefore, despite an apparently immunomodulatory effect, this did not suffice to protect against viral vector-derived α-synuclein-induced neurotoxicity. Further studies are warranted to better elucidate the therapeutic potential of soluble TNF inhibitors in PD.

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organization
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type
Contribution to journal
publication status
epub
subject
in
Neurobiology of Disease
article number
106803
publisher
Elsevier
external identifiers
  • pmid:39800228
ISSN
0969-9961
DOI
10.1016/j.nbd.2025.106803
language
English
LU publication?
yes
additional info
Copyright © 2025. Published by Elsevier Inc.
id
8b30fd74-5d7f-4b2a-8908-e10e6b03825d
date added to LUP
2025-01-13 11:16:07
date last changed
2025-01-13 11:16:07
@article{8b30fd74-5d7f-4b2a-8908-e10e6b03825d,
  abstract     = {{<p>The underlying cause of neuronal loss in Parkinson's disease (PD) remains unknown, but evidence implicates neuroinflammation in PD pathobiology. The pro-inflammatory cytokine soluble tumor necrosis factor (TNF) seems to play an important role and thus has been proposed as a therapeutic target for modulation of the neuroinflammatory processes in PD. In this regard, dominant-negative TNF (DN-TNF) agents are promising antagonists that selectively inhibit soluble TNF signaling, while preserving the beneficial effects of transmembrane TNF. Previous studies have tested the protective potential of DN-TNF-based therapy in toxin-based PD models. Here we test for the first time the protective potential of a DN-TNF therapeutic against α-synuclein-driven neurodegeneration in the viral vector-based PD female rat model. To do so, we administered the DN-TNF agent XPro1595 subcutaneously for a period of 12 weeks. In contrast to previous studies using different PD models, neuroprotection was not achieved by systemic XPro1595 treatment. α-synuclein-induced loss of nigrostriatal neurons, accumulation of pathological inclusions and microgliosis was detected in both XPro1595- and saline-treated animals. XPro1595 treatment increased the percentage of the hypertrophic/ameboid Iba1+ cells in SN and reduced the striatal MHCII+ expression in the α-synuclein-overexpressing animals. However, the treatment did not prevent the MHCII upregulation seen in the SN of the model, nor the increase of CD68+ phagocytic cells. Therefore, despite an apparently immunomodulatory effect, this did not suffice to protect against viral vector-derived α-synuclein-induced neurotoxicity. Further studies are warranted to better elucidate the therapeutic potential of soluble TNF inhibitors in PD.</p>}},
  author       = {{Christiansen, Josefine R and Ferreira, Sara A and Szymkowski, David E and Jakobsson, Johan and Tansey, Malú Gámez and Romero-Ramos, Marina}},
  issn         = {{0969-9961}},
  language     = {{eng}},
  month        = {{01}},
  publisher    = {{Elsevier}},
  series       = {{Neurobiology of Disease}},
  title        = {{Peripherally administered TNF inhibitor is not protective against α-synuclein-induced dopaminergic neuronal death in rats}},
  url          = {{http://dx.doi.org/10.1016/j.nbd.2025.106803}},
  doi          = {{10.1016/j.nbd.2025.106803}},
  year         = {{2025}},
}