Norepinephrine provides short-term neuroprotection against Aβ1-42 by reducing oxidative stress independent of Nrf2 activation.

Research paper by Kyoung A KA Jhang, Eun Ok EO Lee, Hye-Sun HS Kim, Young Hae YH Chong

Indexed on: 24 Jun '14Published on: 24 Jun '14Published in: Neurobiology of Aging


Pathophysiological evidence correlating locus ceruleus neuron loss with increased Alzheimer's disease pathology suggests that norepinephrine (NE) is neuroprotective. Here, we evaluated the effects of NE on amyloid-β (Aβ)1-42-induced neurotoxicity and determined how NE exerts its actions in human SK-N-SH neurons. NE protected SK-N-SH cells against Aβ1-42-induced neurotoxicity only after a 4-hour treatment. The ability of NE to reduce Aβ1-42-induced neurotoxicity was independent of the adrenoceptor signaling pathway. Notably, NE downregulated Aβ1-42-mediated increases in intracellular reactive oxygen species (ROS) production. However, NE did not affect Aβ1-42-induced activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) redox signaling pathway, known to be involved in oxidative stress. Among the antioxidants tested, N-acetyl cysteine and glutathione, which are not only ROS scavengers but also thiol-reducing agents, mimicked the protective effects of NE. Consistently, Kelch-like ECH-associating protein 1 inhibitors, which activated the Nrf2 pathway, failed to decrease Aβ1-42-induced ROS generation and elicited no protection against Aβ1-42. Taken together, these findings suggest that NE could exert neuroprotective function against Aβ1-42 via redox cycling and reduction of intracellular oxidative stress regardless of downstream activation of the Nrf2 pathway.