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. 2021 Jul;17(7):1097-1108.
doi: 10.1002/alz.12276. Epub 2021 Jan 7.

Increased β-site APP cleaving enzyme 1-mediated insulin receptor cleavage in type 2 diabetes mellitus with cognitive impairment

Hong Bao  1 , Yiming Liu  1 , Mengguo Zhang  1 , Zuolong Chen  1 , Weiwei Zhang  2 , Yuhao Ge  2 , Dongmei Kang  2 , Feng Gao  1   2 , Yong Shen  1   2   3
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Increased β-site APP cleaving enzyme 1-mediated insulin receptor cleavage in type 2 diabetes mellitus with cognitive impairment

Hong Bao et al. Alzheimers Dement. 2021 Jul.

Abstract

Introduction: Patients with type 2 diabetes mellitus (T2DM) are at a high risk of cognitive impairment, with insulin resistance playing a pivotal role. β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is considered a predictor of Alzheimer's disease. However, the potential roles of BACE1 in insulin resistance and the risk of cognitive impairment in T2DM remain unclear.

Methods: We measured plasma BACE1 levels, BACE1 cleavage activities for Swedish mutant amyloid precursor protein (APPsw) and insulin receptor β subunit (INSR-β), and soluble INSR (sINSR) levels in a clinical cohort study.

Results: T2DM patients with or without cognitive impairment exhibited elevated plasma BACE1 levels and BACE1 enzymatic activities for APPsw and INSR-β, and sINSR levels. Moreover, the glycemic status correlated with elevated BACE1 levels and BACE1-mediated INSR cleavage, which was associated with insulin resistance.

Discussion: The elevated BACE1 levels in T2DM may contribute to increasing the cognitive impairment risk through both amyloidogenesis and insulin resistance.

Keywords: T2DM with cognitive impairment; cognitive impairment; plasma BACE1 enzymatic activity for APPsw; plasma BACE1 enzymatic activity for INSR-β; plasma BACE1 levels; sINSR levels; type 2 diabetes mellitus.

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