Targeting CD38 immunometabolic checkpoint improves metabolic fitness and cognition in 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 found a unique immune and metabolic signature in CD4+ T cells preceding symptom onset in individuals with familial AD, featured by the elevation of CD38 expression. Using the 5xFAD mouse model of AD, we showed that targeting CD38 evoked a response that restored metabolic fitness, ultimately leading to an improved cognitive performance and attenuated neuroinflammation. Comprehensive profiling across distinct immunological niches, revealed CD4+ T cells residing in the dural meninges as a source of disease-associated IL-17A in 5xFAD mice. Mechanistically, targeting CD38 abrogated TH17-mediated immunity by breaking meningeal-cortical communication through modulation of IL-17A-IL-1? crosstalk. Taken together, these findings suggest CD38 as an immunometabolic checkpoint that could be adopted as a biomarker and may also be therapeutically targeted alone or in combination with other immunotherapies for disease modification in AD