UNLABELLED: The metabolism disorders are a common convergence of Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). The characteristics of AD are senile plaques and neurofibrillary tangles (NFTs) composed by deposits of amyloid-β (Aβ) and phosphorylated tau, respectively. Advanced glycation end-products (AGEs) are a stable modification of proteins by non-enzymatic reactions, which could result in the protein dysfunction. AGEs are associated with some disease developments, such as diabetes mellitus and AD, but the effects of the glycated γ subunit of AMPK on its activity and the roles in AD onset are unknown. METHODS: We studied the effect of glycated γ subunit of AMPK on its activity in N2a cells. In 3 × Tg mice, we administrated L-arginine once every two days for 45 days and evaluated the glycation level of γ subunit and function of AMPK and alternation of pathologies. RESULTS: The glycation level of γ subunit was significantly elevated in 3 × Tg mice as compared with control mice, meanwhile, the level of pT172-AMPK was obviously lower in 3 × Tg mice than that in control mice. Moreover, we found that arginine protects the γ subunit of AMPK from glycation, preserves AMPK function, and improves pathologies and cognitive deficits in 3 × Tg mice. CONCLUSIONS: Arginine treatment decreases glycated γ subunit of AMPK and increases p-AMPK levels in 3 × Tg mice, suggesting that reduced glycation of the γ subunit could ameliorate AMPK function and become a new target for AD therapy in the future.