Rebooting the Immune System: Thymic Rejuvenation Reverses Alzheimer’s Disease Pathogenesis and Cognitive Decline 2255320

Abstract Introduction Alzheimer’s disease (AD), a devastating age-related neurodegenerative disorder, is profoundly linked to immunosenescence. Thymic involution, as a central driver of this process, causes systemic immune collapse. We hypothesized that reversing involution through thymic rejuvenation could mitigate AD by rebooting the systemic immune environment. Methods We longitudinally assessed thymic output in 5XFAD versus wild-type mice, correlating it with brain pathology, and confirmed the age-dependence of thymic decline in human single-cell RNA-seq data. To test our hypothesis, we transplanted neonatal thymic tissue into 6-month-old 5XFAD mice and assessed thymic output, peripheral T cell profiles, Aβ load, microgliosis, and cognitive function. Systemic and neuroimmune changes were profiled by single-cell RNA-seq. Furthermore, we engineered and transplanted T cell—deficient mouse thymic tissue chips (MTTCs) to evaluate their therapeutic efficacy and translational potential. Results Thymic involution was driven by aging, not AD pathology, in both mice and humans. This functional decline strongly correlated with Aβ burden and microgliosis. Neonatal thymic transplantation robustly enhanced thymic output, which was associated with a ∼45% reduction in Aβ plaques, suppressed microgliosis, and rescued cognitive function. Single cell transcriptomics revealed a reversal of immunosenescent signatures in the periphery and a concomitant reprogramming of disease-associated microglia (DAM) in the brain. Crucially, transplantation of MTTCs recapitulated these therapeutic benefits, demonstrating clinical potential. Conclusion We introduce a paradigm-shifting therapeutic strategy for AD: thymic rejuvenation. By rebooting the aged immune landscape, this approach reverses established neuropathology and rescues cognitive decline, moving beyond single molecular targets in the brain. It thereby establishes a novel class of “immunoregenerative” therapeutics that combat neurodegeneration by restoring systemic immune homeostasis. Funding Source National Natural Science Foundation of China (82502227), Science and Technology Innovation Key R&D Program of Chongqing (CSTB2023TIAD-STX0041), Chongqing International Institute for Immunology-Innovative Basic Research Project (2023YJC02), Brain-Gain Topic Categories Neuroimmunology (NEUR)