Scholarlink

<p>Protective immunity, essential for brain maintenance and repair, may be compromised in Alzheimer’s disease (AD). Here, using high-dimensional single-cell mass cytometry, we find a unique immunometabolic signature in circulating CD4<sup>+</sup> T cells preceding symptom onset in individuals with familial AD, featured by the elevation of CD38 expression. Using female 5xFAD mice, a mouse model of AD, we show that treatment with an antibody directed to CD38 leads to restored metabolic fitness, improved cognitive performance, and attenuated local neuroinflammation. Comprehensive profiling across distinct immunological niches in 5xFAD mice, reveals a high level of disease-associated CD4<sup>+</sup> T cells that produce IL-17A in the dural meninges, previously linked to cognitive decline. Targeting CD38 leads to abrogation of meningeal T<sub>H</sub>17 immunity and cortical IL-1β, breaking the negative feedback loop between these two compartments. Taken together, the present findings suggest CD38 as an immunometabolic checkpoint that could be adopted as a pre-symptomatic biomarker for early diagnosis of AD, and might also be therapeutically targeted alone or in combination with other immunotherapies for disease modification.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Targeting CD38 immunometabolic checkpoint improves metabolic fitness and cognition in a mouse model of Alzheimer’s disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月20日

查看全文
  • Javier María Peralta Ramos,
  • Giulia Castellani,
  • Denise Kviatcovsky,
  • Tommaso Croese,
  • Afroditi Tsitsou-Kampeli,
  • Chiara Burgaletto,
  • Miguel Angel Abellanas,
  • Liora Cahalon,
  • Sarah Phoebeluc Colaiuta,
  • Tomer-Meir Salame,
  • Yael Kuperman,
  • Alon Savidor,
  • Maxim Itkin,
  • Sergey Malitsky,
  • Sharon Ovadia,
  • Shir Ferrera,
  • Limor Kalfon,
  • Shiran Kadmani,
  • Nadra Samra,
  • Rotem Paz,
  • Lior Rokach,
  • Roberto Furlan,
  • Judith Aharon-Peretz,
  • Tzipora C. Falik-Zaccai,
  • Michal Schwartz

摘要

Protective immunity, essential for brain maintenance and repair, may be compromised in Alzheimer’s disease (AD). Here, using high-dimensional single-cell mass cytometry, we find a unique immunometabolic signature in circulating CD4+ T cells preceding symptom onset in individuals with familial AD, featured by the elevation of CD38 expression. Using female 5xFAD mice, a mouse model of AD, we show that treatment with an antibody directed to CD38 leads to restored metabolic fitness, improved cognitive performance, and attenuated local neuroinflammation. Comprehensive profiling across distinct immunological niches in 5xFAD mice, reveals a high level of disease-associated CD4+ T cells that produce IL-17A in the dural meninges, previously linked to cognitive decline. Targeting CD38 leads to abrogation of meningeal TH17 immunity and cortical IL-1β, breaking the negative feedback loop between these two compartments. Taken together, the present findings suggest CD38 as an immunometabolic checkpoint that could be adopted as a pre-symptomatic biomarker for early diagnosis of AD, and might also be therapeutically targeted alone or in combination with other immunotherapies for disease modification.