Abstract: Objective To observe the effects of high-fat diet-induced insulin resistance on amino acid homeostasis in APP/PS1 double transgenic mice. Methods Twenty male APP/ PS1 double transgenic mice aged 3 months were randomly divided into two groups and fed on the normal diet（ND）and high-fat diet（HFD），respectively. At the end of 20 weeks，the glucose tolerance test（GTT） and insulin tolerance test（ITT） were performed，the area under the curve（AUC）was calculated，and insulin sensitivity was evaluated. Then the mice were sacrificed， and the serum and hippocampus were collected. Aβ40/Aβ42 concentration in the hippocampus was measured by ELISA. Ultrastructure in the hippocampus was observed by the electron microscope. The serum levels of amino acids were measured by ultra-high performance liquid chromatography- tandem mass spectrometry（HPLC-MS/MS）. Results The AUC of ITT and GTT were significantly increased after 20-week HFD feeding compared with ND mice. In HFD-fed mice，the levels of Aβ40/Aβ42 in the hippocampus were significantly increased，and ultrastructure damage to the hippocampus was exacerbated than that of mice fed with ND. Serum leucine，isoleucine，cysteine，glutamine，glycine，and serine levels were significantly decreased compared with ND mice. Conclusion HFD-induced insulin resistance exacerbates ADrelated pathogenesis and is accompanied by amino acid dysmetabolism. However，the causal relationship and underlying mechanisms between amino acid dysmetabolism and AD pathology should be studied further.

Key words: Alzheimer′s disease, insulin resistance, amino acids homeostasis, high-fat diet