Legumain in the brain of animal models of Alzheimer’s disease (AD) and its promise to be an intervention target for AD

Abstract

Age is the greatest risk factor for most cases of Alzheimer's disease (AD) as the incidence rises significantly with ageing. Mammalian legumain, a lysosomal asparaginyl endopeptidase recently was suggested as a potential link between aging and AD onset. Herein, we inspected age-related legumain regulation in two animal models of AD and tested its promise to be an intervention target for AD. Male APPswe/PS1dE9 transgenic and the senescence-accelerated mouse prone 8 (SAMP8) mice are the two AD animal models. The age-related expression and activity of legumain in brain tissue of these mice were detected using western blot and enzymatic activity assay. Immunohistochemically staining and Morris water maze test were used to reveal pathological changes in the brain and monitor cognition decline. Mice were administrated with a δ-secretase inhibitor 11 (10 mg/kg, p.o.) once daily for 3 months to suppress brain legumain activity and modify AD-like pathology. The expression level and enzymatic activity of legumain was up-regulated in brains of 5-8-month old SAMP8 and APPswe/PS1dE9 transgenic mice in comparison with age-mated WT mice. Elevation of legumain preceded formation of Aβ plaque and cognitive impairment. Pharmacological inhibition of legumain reduced Aβ production and tau hyperphosphorylation, rescued degeneration of neuronal structural integrity in the cortex and hippocampus of AD mice and attenuated memory loss. In SMAP8 and its control strain SAMR1 mice, the enzymatic activity of brain legumain is almost 20 times lower than that in kidney and liver tissue. Inhibition of brain legumain didn't incur severe side effect. Elevated legumain in a certain brain region can be considered as an abnormal condition and a potential intervention target for neurodegenerative disease, such as AD. But how legumain was up-regulated and activated in the brain of AD model mice remains to be elucidated. Acknowledgements: Mingke Song and this study is supported by the National Natural Science Foundation of China, China (No. 91949116, No.81873807) and Innovative Research Team of High-level Local Universities in Shanghai, China.