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

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 and Michal Schwartz ()
Additional contact information
Javier María Peralta Ramos: Weizmann Institute of Science
Giulia Castellani: Weizmann Institute of Science
Denise Kviatcovsky: Weizmann Institute of Science
Tommaso Croese: Weizmann Institute of Science
Afroditi Tsitsou-Kampeli: Weizmann Institute of Science
Chiara Burgaletto: Weizmann Institute of Science
Miguel Angel Abellanas: Weizmann Institute of Science
Liora Cahalon: Weizmann Institute of Science
Sarah Phoebeluc Colaiuta: Weizmann Institute of Science
Tomer-Meir Salame: Weizmann Institute of Science
Yael Kuperman: Weizmann Institute of Science
Alon Savidor: Weizmann Institute of Science
Maxim Itkin: Weizmann Institute of Science
Sergey Malitsky: Weizmann Institute of Science
Sharon Ovadia: Weizmann Institute of Science
Shir Ferrera: Weizmann Institute of Science
Limor Kalfon: Galilee Medical Center
Shiran Kadmani: Galilee Medical Center
Nadra Samra: Galilee Medical Center
Rotem Paz: Rambam Health Care Campus
Lior Rokach: Ben Gurion University of the Negev
Roberto Furlan: IRCCS Ospedale San Raffaele
Judith Aharon-Peretz: Rambam Health Care Campus
Tzipora C. Falik-Zaccai: Galilee Medical Center
Michal Schwartz: Weizmann Institute of Science

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-58494-y

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