High-intensity interval training and moderate-intensity continuous training improve hippocampal synaptic plasticity in Alzheimer's disease via differential lactylation.

While both high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) are known to benefit physical health, their comparative effects on cognitive function in Alzheimer's disease (AD) remain unclear. Here, using equal number 3.5 months old male (28 ± 2 g) and female (24.0 ± 1.1 g) 5 × FAD transgenic mice, we demonstrate that HIIT and MICT improve AD pathology and cognitive performance, as evidenced by reduced amyloid-β deposition and enhanced hippocampal synaptic plasticity. Both exercise modalities significantly elevated lactate levels in the blood and hippocampus of AD mice. The functional consequences of this increase, however, were not linear. We found that while low lactate (2 mM) universally enhanced excitatory postsynaptic potentials in the hippocampus, high lactate (7 mM) was inhibitory, with no significant effects observed at intermediate concentrations (4 and 6 mM), an effect independent of genotype. To mechanistically link lactate dynamics to functional benefits, we performed lactylation-based proteomics. This revealed that HIIT and MICT differentially modulated protein lactylation-both reduced lactylation of glutamatergic synaptic proteins, but HIIT specifically upregulated lactylation of necroptosis-related proteins (CypA/Cyp40), while MICT downregulated proteasome-related proteins (Psmc1/Psmα7). Our findings suggest that exercise-induced lactate dynamically regulates brain function via protein lactylation, offering a novel therapeutic avenue for AD.