Fructo-oligosaccharides (FOS), an important prebiotic, have been proved to have a beneficial effect on Alzheimer's disease (AD); however, the specific mechanism remains to be confirmed. Senile plaques are one of the main neuropathological features of AD and the core of senile plaques mainly consists of extracellular beta-amyloid (Aβ). Reducing Aβ accumulation in the brain is an important therapeutic strategy for AD. Neprilysin (NEP), a major Aβ-degrading enzyme, has been found to be decreased in the AD brain. Evidence has shown that the expression of NEP is associated with histone acetylation levels. Histone deacetylases (HDACs) are the key enzymes in the modulation of histone acetylation modification. Importantly, several metabolites of FOS have been demonstrated to be pan-HDAC inhibitors. In this study, we demonstrate that FOS ameliorate cognitive impairment and alleviate Aβ accumulation in the brain of AD model mice. The regulation of HDAC2 on NEP plays an important role in the anti-AD effect of FOS.