Photobiomodulation of immune crosstalk rescues neuroinflammation in Alzheimer's disease models.
Peripheral immune cell infiltration and crosstalk with brain-resident cells critically drive Alzheimer's disease (AD)-associated neuroinflammation, highlighting its therapeutic potential. Here, we found that photobiomodulation (PBM) markedly reduced cerebral CD8+ T cells infiltration in the cortex of AD (APP/PS1 and 3×Tg) mice, thereby improving cognition, and alleviating AD-related pathology by mitigating neuronal damage and gliosis. Immunofluorescence and transcriptomic analyses revealed that PBM inhibited the release of chemokines and pro-inflammatory cytokines from microglia, reducing endothelial adhesion molecules-mediated T cell migration. Concurrently, reduced secretion of tumor necrosis factor-α, interleukin-1α, and complement component 1q by pro-inflammatory microglia further diminished neurotoxic A1 astrocyte induction. Genetic overexpression or pharmacological inhibition further validated that PBM disrupted microglia NOD-like receptor protein 3 inflammasomes activation, attenuating astrocyte reactivity and T cells recruitment. These findings collectively suggest that the PBM-induced modulation of crosstalk between microglia, astrocytes, and CD8+ T cells is closely related to cognitive improvement. Reprogramming central-peripheral immune crosstalk with PBM resolves neuroinflammation and restores cognition in AD models-a translatable strategy for combating neurodegeneration.