Targeting CD38 immunometabolic checkpoint improves metabolic fitness and cognition in a mouse model of Alzheimer’s disease
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.
Authors
- Afroditi Tsitsou-Kampeli (ORCID: https://orcid.org/0000-0002-8600-2001)
- Tomer‐Meir Salame (ORCID: https://orcid.org/0000-0003-4260-8738)
- Chiara Burgaletto (ORCID: https://orcid.org/0000-0002-5517-8223)
- Sergey Malitsky (ORCID: https://orcid.org/0000-0003-4619-7219)
- Lior Rokach (ORCID: https://orcid.org/0000-0002-6956-3341)
- Limor Kalfon
- Tzipora C. Falik‐Zaccai (ORCID: https://orcid.org/0000-0003-0065-1922)
- S Ovadia
- Sarah Phoebeluc Colaiuta (ORCID: https://orcid.org/0000-0002-9071-9857)
- Denise Kviatcovsky (ORCID: https://orcid.org/0000-0002-9697-0380)
- Alon Savidor (ORCID: https://orcid.org/0000-0001-8884-6948)
- Shir Ferrera
- Miguel Angel Abellanas (ORCID: https://orcid.org/0000-0002-5680-1582)
- Roberto Furlan (ORCID: https://orcid.org/0000-0001-7376-9425)
- Liora Cahalon
- Yael Kuperman (ORCID: https://orcid.org/0000-0003-3830-1856)
- Javier María Peralta Ramos (ORCID: https://orcid.org/0000-0001-9730-9001)
- Rotem Paz
- Maxim Itkin (ORCID: https://orcid.org/0000-0003-1348-2814)
- Giulia Castellani (ORCID: https://orcid.org/0000-0002-0611-5250)
- Tommaso Croese (ORCID: https://orcid.org/0000-0002-3805-3429)
- Michal Schwartz (ORCID: https://orcid.org/0000-0003-4015-7507)
- Judith Aharon‐Peretz
- Nadra Nasser Samra
- Shiran Kadmani
Institutions
- Ben-Gurion University of the Negev (IL)
- Bar-Ilan University (IL)
- Technion – Israel Institute of Technology (IL)
- Western Galilee Hospital (IL)
- Rambam Health Care Campus (IL)
- IRCCS Ospedale San Raffaele (IT)
- Weizmann Institute of Science (IL)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-20
- DOI
- https://doi.org/10.1038/s41467-025-58494-y
- Citations
- 3
- Primary Topic
- Calcium signaling and nucleotide metabolism
- Type
- article
- Field-Weighted Citation Impact
- 3.35
Funders
- Fundación Ramón Areces
- Weizmann Institute of Science
- Israel Science Foundation