Rifampicin Suppresses Amyloid-β Accumulation Through Enhancing Autophagy in the Hippocampus of a Lipopolysaccharide-Induced Mouse Model of Cognitive Decline

Article type: Research Article

Authors: Zhu, Lihong^{a; 1} | Yuan, Qiongru^{b; 1} | Zeng, Zhaohao^b | Zhou, Ruiyi^b | Luo, Rixin^b | Zhang, Jiawei^a | Tsang, Chi Kwan^c | Bi, Wei^{b; c; *}

Affiliations: [a] Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, PR China | [b] Department of Neurology, The First Affiliated Hospital of Jinan University, Guangzhou, PR China | [c] Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, Guangzhou, PR, China

Correspondence: [*] Correspondence to: Wei Bi, Department of Neurology, The First Affiliated Hospital of Jinan University, Guangzhou 510630, PR China. biwei4762@sina.com

Note: [1] These authors contributed equally to this work.

Abstract: Background:Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) deposition. The metabolism of Aβ is critically affected by autophagy. Although rifampicin is known to mediate neuroinflammation, the underlying mechanism by which rifampicin regulates the cognitive sequelae remains unknown. Objective:Based on our previous findings that rifampicin possesses neuroprotective effects on improving cognitive function after neuroinflammation, we aimed to examine in this study whether rifampicin can inhibit Aβ accumulation by enhancing autophagy in a mouse model of lipopolysaccharide (LPS)-induced cognitive impairment. Methods:Adult C57BL/6 mice were intraperitoneally injected with rifampicin, chloroquine, and/or LPS every day for 7 days. Pathological and biochemical assays and behavioral tests were performed to determine the therapeutic effect and mechanism of rifampicin on the hippocampus of LPS-induced mice. Results:We found that rifampicin ameliorated cognitive impairments in the LPS-induced mice. In addition, rifampicin attenuated the inhibition of autophagosome formation, suppressed the accumulation of Aβ1–42, and protected the hippocampal neurons against LPS-induced damage. Our results further demonstrated that rifampicin improved the neurological function by promoting autophagy through the inhibition of Akt/mTOR/p70S6K signaling pathway in the hippocampus of LPS-induced mice. Conclusion:Rifampicin ameliorates cognitive impairment by suppression of Aβ1–42 accumulation through inhibition of Akt/mTOR/p70S6K signaling and enhancement of autophagy in the hippocampus of LPS-induced mice.

Keywords: Alzheimer’s disease, amyloid-β, autophagy, cognitive impairment, neuroinflammation, rifampicin

DOI: 10.3233/JAD-200690

Journal: Journal of Alzheimer's Disease, vol. 79, no. 3, pp. 1171-1184, 2021