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<p>Toxic signaling of oligomeric protein species via binding to the cellular prion protein (PrP<sup>C</sup>) is implicated in various neurodegenerative diseases, including Alzheimer’s (AD) and Parkinson’s disease (PD). Metabotropic glutamate receptor 5 (mGluR5) has been identified as a PrP<sup>C</sup> signaling partner, and pharmacological inhibition of mGluR5 was shown to improve cognitive performance and rescue long-term-potentiation (LTP) impairment in both in vitro and in vivo models of AD and PD. Prion diseases are another group of fatal neurodegenerative disorders that are characterized by templated misfolding of endogenous PrP<sup>C</sup> itself into the disease-driving counterpart PrP<sup>Sc</sup>. Besides its role in the self-propagating misfolding cascade and aggregation, PrP<sup>Sc</sup> also acts as a toxic PrP<sup>C</sup> ligand in aberrant signaling through mGluR5. Therefore, targeting metabotropic glutamate receptors has been proposed as a therapeutic strategy for the intervention of prion disease. In this study, we investigated the impact of long-term oral administration of two different selective mGluR5 inhibitors, the negative allosteric inhibitor CTEP and a <i>Silent Allosteric</i> mGluR5 <i>Modulator</i> (SAM), in a mouse model of prion disease. Our findings demonstrate that treatment initiated during the preclinical phase significantly prolonged the survival of mice, whereas treatment starting after the onset of symptoms was no longer effective. Early treatment also delayed the formation of spongiosis, a pathological hallmark of prion diseases, but did not alter PrP<sup>Res</sup> levels. Preclinical dysregulation of mGluR5 could be shown in the mouse and a non-human primate model for prion diseases. Interestingly, in primary neurons, subacute treatment with CTEP blocked Aβ-induced, but not PrP<sup>Sc</sup>-associated synaptotoxicity. Thus, modes of action might differ markedly from those observed in models of Alzheimer’s disease. Together, although our data show that targeting mGluR5 may be an efficient therapy, however, since treatment needs to be started early during prion disease progression, the narrow therapeutic window limits its therapeutic application in human prion diseases.</p>

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Presymptomatic pharmacological inhibition of mGluR5 improves survival in a mouse model of prion diseases

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月29日

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  • Yue Wang,
  • Behnam Mohammadi,
  • Christiane Hartmann,
  • Kristin Hartmann,
  • Edda Thies,
  • Andreu Matamoros-Angles,
  • Cheng Fang,
  • David A. Harris,
  • Jörg Tatzelt,
  • Hermann C. Altmeppen,
  • Diego Sepulveda-Falla,
  • Stephen M. Strittmatter,
  • Markus Glatzel,
  • Susanne Krasemann

摘要

Toxic signaling of oligomeric protein species via binding to the cellular prion protein (PrPC) is implicated in various neurodegenerative diseases, including Alzheimer’s (AD) and Parkinson’s disease (PD). Metabotropic glutamate receptor 5 (mGluR5) has been identified as a PrPC signaling partner, and pharmacological inhibition of mGluR5 was shown to improve cognitive performance and rescue long-term-potentiation (LTP) impairment in both in vitro and in vivo models of AD and PD. Prion diseases are another group of fatal neurodegenerative disorders that are characterized by templated misfolding of endogenous PrPC itself into the disease-driving counterpart PrPSc. Besides its role in the self-propagating misfolding cascade and aggregation, PrPSc also acts as a toxic PrPC ligand in aberrant signaling through mGluR5. Therefore, targeting metabotropic glutamate receptors has been proposed as a therapeutic strategy for the intervention of prion disease. In this study, we investigated the impact of long-term oral administration of two different selective mGluR5 inhibitors, the negative allosteric inhibitor CTEP and a Silent Allosteric mGluR5 Modulator (SAM), in a mouse model of prion disease. Our findings demonstrate that treatment initiated during the preclinical phase significantly prolonged the survival of mice, whereas treatment starting after the onset of symptoms was no longer effective. Early treatment also delayed the formation of spongiosis, a pathological hallmark of prion diseases, but did not alter PrPRes levels. Preclinical dysregulation of mGluR5 could be shown in the mouse and a non-human primate model for prion diseases. Interestingly, in primary neurons, subacute treatment with CTEP blocked Aβ-induced, but not PrPSc-associated synaptotoxicity. Thus, modes of action might differ markedly from those observed in models of Alzheimer’s disease. Together, although our data show that targeting mGluR5 may be an efficient therapy, however, since treatment needs to be started early during prion disease progression, the narrow therapeutic window limits its therapeutic application in human prion diseases.