Amyloid β， a key molecule in the pathogenesis of Alzheimer's disease (AD)， is produced from amyloid precursor protein (APP) by the cleavage of secretases. APP is SUMOylated near the cleavage site of β-secretase. SUMOylation of APP reduces amyloid β production， but its regulatory system is still unclear. SUMOylation， a modification at a lysine residue of a target protein， is mediated by activating， conjugating， and ligating enzymes and is reversed by a family of sentrin/SUMO-specific proteases (SENPs). Here， we found that both SENP1 and SENP2 induced de-SUMOylation of APP. Using quantitative PCR， we also found that expression of SENP1 but not SENP2 increased in an age-dependent manner only in female mice. The results of immunoblot analyses showed that the protein expression was consistent with the PCR results. Females， compared to males， have a higher incidence of AD in humans and show more aggressive amyloid pathology in AD mouse models. Our results provide a clue to understanding the role of SUMOylation in the sex difference in AD pathogenesis.