Legumain Knockout Protects Against Aβ1-42-Induced AD-like Cognitive Deficits and Synaptic Plasticity Dysfunction Via Inhibiting Neuroinflammation Without Cleaving APP

Abstract

Neuroinflammation is the important pathological feature of Alzheimer's disease (AD). Legumain, a lysosomal cysteine protease, plays an important role in neuroinflammation during ischemic stroke and depressive disorder. Legumain is involved in AD process through cleaving APP; however, it is unclear if legumain can possibly modulate neuroinflammation without cleaving APP in AD. Thus, we established a mouse model of AD by single intracerebroventricular injections of Aβ_1-42 in legumain knockout (KO) mice. The behavioral tests showed that legumain-KO effectively ameliorated cognitive impairment induced by Aβ_1-42. Moreover, legumain deprivation significantly improves the synaptic plasticity damages in Aβ_1-42-treated mice. Moreover, legumain-KO considerably inhibited the activation of microglia and reduced the expression of inflammatory cytokines in the hippocampus of Aβ_1-42-treated mice. Interestingly, we found that legumain-KO inhibited TLR4/MyD88/NF-κB pathway, which was activated by Aβ_1-42 in the hippocampus. In conclusion, our results suggested that legumain-KO reduced the level of neuroinflammation that was associated with inhibiting TLR4/MyD88/NF-κB pathways, thereby improving the hippocampal synaptic plasticity and reducing the cognitive impairments in Aβ_1-42-treated mice. Legumain knockout blocked microglia activation by inhibiting TLR4/MyD88/NF-κB signaling pathways, and further reduced inflammatory cytokine expression. As a result, legumain knockout alleviated synaptic damage and cognitive impairment induced by Aβ1--42.

Keywords: Alzheimer’s disease; Cognitions; Legumain; Neuroinflammation; Synaptic plasticity.