Scavenging Reactive Oxygen Species Decreases Amyloid-β Levels via Activation of PI3K/Akt/GLUT1 Pathway in N2a/APP695swe Cells

Article type: Research Article

Authors: Peng, Yan^a | Zhang, Li^b | Zhou, Fanlin^c | Wang, Yangyang^c | Zhang, Xiong^a | Fan, Jianing^c | Li, Shijie^c | Li, Xiaoju^c | Li, Yu^{a; c; *}

Affiliations: [a] Institute of Neuroscience, School of Basic Medicine, Chongqing Medical University, Chongqing, China | [b] Department of Pathophysiology, Chongqing Medical University, Chongqing, China | [c] Department of Pathology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China

Correspondence: [*] Correspondence to: Yu Li, Institute of Neuroscience, School of Basic Medicine, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, Chongqing 400016, China. Tel.: +86 15826412362; E-mail: [email protected].; ORCID: 0000-0003-1301-7234.

Abstract: Background:Dysregulated glucose metabolism in the brain is considered to be one of the key causes of Alzheimer’s disease (AD). Abnormal glucose uptake in AD is tightly associated with decreased levels of glucose transporter 1 (GLUT1) and GLUT3 in the brain, but the underlying mechanisms remain unclear. Objective:We aimed to explore the cause and mechanism of impaired glucose uptake in AD. Methods:N2a/WT and N2a/APP695swe cells were cultured in vitro, and cellular glucose uptake and ATP content, as well as the expression of GLUT1, GLUT3, and PI3K/Akt pathway members, were detected. Intracellular reactive oxygen species (ROS) levels were detected by flow cytometry. After treatment with the ROS scavenger N-acetyl-L-cysteine (NAC), the above indicators were detected again. Results:GLUT1 expression was significantly decreased (p = 0.0138) in N2a/APP695swe cells, while GLUT3 expression was no statistical difference (p > 0.05). After NAC treatment, PI3K and Akt phosphorylation levels, GLUT1 expression, glucose uptake and ATP levels were remarkably increased (p = 0.0006, p = 0.0008, p = 0.0009, p = 0.0001, p = 0.0013), while Aβ levels were significantly decreased (p = 0.0058, p = 0.0066). After addition of the PI3K inhibitor LY29004, GLUT1 expression was reduced (p = 0.0008), and Aβ levels were increased (p = 0.0009, p = 0.0117). In addition, increases in glucose uptake and ATP levels induced by the Akt activator SC79 were hindered by the GLUT1 inhibitor WZB117 (p = 0.0002, p = 0.0005). Aβ levels were decreased after SC79 treatment and increased after WZB117 treatment (p = 0.0212, p = 0.0006). Conclusion:Taken together, scavenging of ROS prevents from Aβ deposition via activation of the PI3K/Akt/GLUT1 pathway, and improved the impaired glucose uptake in N2a/APP695swe cells.

Keywords: Alzheimer’s disease, glucose uptake, GLUT1, PI3K/Akt, reactive oxygen species

DOI: 10.3233/JAD-220610

Journal: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 185-198, 2022