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; Michal Schwartz

doi:10.1038/s41467-025-58494-y

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, Michal Schwartz^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

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 T_H17 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.

Original language	English
Article number	3736
Number of pages	17
Journal	Nature Communications
Volume	16
DOIs	https://doi.org/10.1038/s41467-025-58494-y
Publication status	Published - 20 Apr 2025

Funding

We thank the members of the Schwartz lab and Weizmann Institute of Science for insightful discussions, and apologize to colleagues whose work was not included due to space constraints. We especially thank R. Valdés-Mas for providing critical feedback on bioinformatic analyses, C. Raanan, I. Biton, O. Rosenberg, N. Stettner, T. Mehlman, and A. Brandis for technical support, and S. Schwarzbaum for proofreading the manuscript. J.M.P.R. and G.C. received a Senior Postdoctoral Fellowship from the Weizmann Institute of Science. M.A.A. received a postdoctoral fellowship from Fundación Ramón Areces. The work was supported by an Advanced European Research Council grant (N° 741744), the Israel Science Foundation (ISF, grant No. 991/16), the ISF-Legacy Heritage Biomedical Science Partnership (grant No. 135 4/15), the Thompson Foundation and the Adelis Foundation (given to M.S.). We thank the members of the Schwartz lab and Weizmann Institute of Science for insightful discussions, and apologize to colleagues whose work was not included due to space constraints. We especially thank R. Valdés-Mas for providing critical feedback on bioinformatic analyses, C. Raanan, I. Biton, O. Rosenberg, N. Stettner, T. Mehlman, and A. Brandis for technical support, and S. Schwarzbaum for proofreading the manuscript. J.M.P.R. and G.C. received a Senior Postdoctoral Fellowship from the Weizmann Institute of Science. M.A.A. received a postdoctoral fellowship from Fundación Ramón Areces. The work was supported by an Advanced European Research Council grant (N° 741744), the Israel Science Foundation (ISF, grant No. 991/16), the ISF-Legacy Heritage Biomedical Science Partnership (grant No. 135 4/15), the Thompson Foundation and the Adelis Foundation (given to M.S.).

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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Peralta Ramos, J. M., Castellani, G., Kviatcovsky, D., Croese, T., Tsitsou-Kampeli, A., Burgaletto, C., Abellanas, M. A., Cahalon, L., Phoebeluc Colaiuta, S., Salame, T. M., Kuperman, Y., Savidor, A., Itkin, M., Malitsky, S., Ovadia, S., Ferrera, S., Kalfon, L., Kadmani, S., Samra, N., ... Schwartz, M. (2025). Targeting CD38 immunometabolic checkpoint improves metabolic fitness and cognition in a mouse model of Alzheimer’s disease. Nature Communications, 16, Article 3736. https://doi.org/10.1038/s41467-025-58494-y

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title = "Targeting CD38 immunometabolic checkpoint improves metabolic fitness and cognition in a mouse model of Alzheimer{\textquoteright}s disease",

abstract = "Protective immunity, essential for brain maintenance and repair, may be compromised in Alzheimer{\textquoteright}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.",

author = "\{Peralta Ramos\}, \{Javier Mar{\'i}a\} and Giulia Castellani and Denise Kviatcovsky and Tommaso Croese and Afroditi Tsitsou-Kampeli and Chiara Burgaletto and Abellanas, \{Miguel Angel\} and Liora Cahalon and \{Phoebeluc Colaiuta\}, Sarah and Salame, \{Tomer Meir\} and Yael Kuperman and Alon Savidor and Maxim Itkin and Sergey Malitsky and Sharon Ovadia and Shir Ferrera and Limor Kalfon and Shiran Kadmani and Nadra Samra and Rotem Paz and Lior Rokach and Roberto Furlan and Judith Aharon-Peretz and Falik-Zaccai, \{Tzipora C.\} and Michal Schwartz",

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Peralta Ramos, JM, Castellani, G, Kviatcovsky, D, Croese, T, Tsitsou-Kampeli, A, Burgaletto, C, Abellanas, MA, Cahalon, L, Phoebeluc Colaiuta, S, Salame, TM , Kuperman, Y , Savidor, A , Itkin, M , Malitsky, S, Ovadia, S, Ferrera, S, Kalfon, L, Kadmani, S, Samra, N, Paz, R, Rokach, L, Furlan, R, Aharon-Peretz, J, Falik-Zaccai, TC & Schwartz, M 2025, 'Targeting CD38 immunometabolic checkpoint improves metabolic fitness and cognition in a mouse model of Alzheimer’s disease', Nature Communications, vol. 16, 3736. https://doi.org/10.1038/s41467-025-58494-y

TY - JOUR

T1 - Targeting CD38 immunometabolic checkpoint improves metabolic fitness and cognition in a mouse model of Alzheimer’s disease

AU - Peralta Ramos, Javier María

AU - Castellani, Giulia

AU - Kviatcovsky, Denise

AU - Croese, Tommaso

AU - Tsitsou-Kampeli, Afroditi

AU - Burgaletto, Chiara

AU - Abellanas, Miguel Angel

AU - Cahalon, Liora

AU - Phoebeluc Colaiuta, Sarah

AU - Salame, Tomer Meir

AU - Kuperman, Yael

AU - Savidor, Alon

AU - Itkin, Maxim

AU - Malitsky, Sergey

AU - Ovadia, Sharon

AU - Ferrera, Shir

AU - Kalfon, Limor

AU - Kadmani, Shiran

AU - Samra, Nadra

AU - Paz, Rotem

AU - Rokach, Lior

AU - Furlan, Roberto

AU - Aharon-Peretz, Judith

AU - Falik-Zaccai, Tzipora C.

AU - Schwartz, Michal

PY - 2025/4/20

Y1 - 2025/4/20

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105003189185

U2 - 10.1038/s41467-025-58494-y

DO - 10.1038/s41467-025-58494-y

M3 - Article

AN - SCOPUS:105003189185

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

M1 - 3736

ER -

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

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