Amyloid-β_25–35 Upregulates Endogenous Neuroprotectant Neuroglobin via NFκB Activation in vitro

Article type: Research Article

Authors: Liu, Ning^{a; d} | Yu, Zhanyang^{d; *} | Xun, Yu^b | Shu, Pan^b | Yue, Yiwei^{c; d} | Yuan, Shishan^a | Jiang, Yinghua^d | Huang, Zixuan^a | Yang, Xiaoping^a | Feng, Xing^a | Xiang, Shuanglin^b | Wang, Xiaoying^{d; *}

Affiliations: [a] Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China | [b] Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Sciences, Hunan Normal University, Changsha, China | [c] School of Clinical Medicine, Zhengzhou University, Zhengzhou, China | [d] Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

Correspondence: [*] Correspondence to: Zhanyang Yu, PhD, Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Room 2401, Charlestown, MA 02129, USA. Tel.: +1 617 724 9503; E-mail: [email protected] and Xiaoying Wang, PhD, Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Room 2401, Charlestown, MA 02129, USA. Tel.: +1 617 724 9513; E-mail: [email protected].

Abstract: Neuroglobin (Ngb) has been reported to be increased in early and moderately advanced Alzheimer’s disease (AD) stages but declined in the severe stage. However, its regulatory mechanisms and pathophysiological roles in the disease remain to be defined. In this study, we found that Ngb expression was significantly upregulated by low dose Aβ25–35, the neurotoxic fragment of Aβ1 - 40 and Aβ1 - 42, but was not further increased by a higher dose of Aβ25–35. Mutation analysis and supershift assay demonstrated that transcription factor Nuclear Factor κB (NFκB), κB2 and κB3 sites located in mouse Ngb promoter region were involved in dynamic regulation of Ngb expression in response to different doses of Aβ25–35 stimulation. In addition, we found that suppression of endogenous Ngb expression exacerbated Aβ25–35-induced neuronal cell death and mitochondrial dysfunction. Our results indicate that endogenous Ngb expression may be upregulated by low dose Aβ25–35, which is responsible for protecting against Aβ25–35-mediated neurotoxicity. These experimental findings suggest that upregulation of endogenous Ngb expression might be an effective intervention approach for AD.

Keywords: Alzheimer’s disease, amyloid-β, mitochondria, neuroglobin, neurotoxicity, NFκB

DOI: 10.3233/JAD-180163

Journal: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1163-1174, 2018