Reinforcing Nrf2 Signaling: Help in the Alzheimer's Disease Context

Abstract

Oxidative stress plays a role in various pathophysiological diseases, including neurogenerative diseases, such as Alzheimer's disease (AD), which is the most prevalent neuro-pathology in the aging population. Oxidative stress has been reported to be one of the earliest pathological alterations in AD. Additionally, it was demonstrated that in older adults, there is a loss of free radical scavenging ability. The Nrf2 transcription factor is a key regulator in antioxidant defense systems, but, with aging, both the amount and the transcriptional activity of Nrf2 decrease. With the available treatments for AD being poorly effective, reinforcing the antioxidant defense systems via the Nrf2 pathway may be a way to prevent and treat AD. To highlight the predominant role of Nrf2 signaling in defending against oxidative stress and, therefore, against neurotoxicity, we present an overview of the natural compounds that exert their own neuroprotective roles through the activation of the Nrf2 pathway. This review is an opportunity to promote a holistic approach in the treatment of AD and to highlight the need to further refine the development of new potential Nrf2-targeting drugs.

Keywords: Alzheimer’s disease; Nrf2; flavonoid compounds; natural compounds; oxidative stress.

Figure 1

Domain architecture of the Nrf2 protein and molecular interactions.

Figure 2

Physiological mechanisms of the Keap1-dependent and independent regulation of Nrf2. Oxidative stress leads to the positive regulation of the Nrf2 pathway by releasing Nrf2 from Keap1. The p62 increases Nrf2 translocation, triggering an autophagic degradation of Keap1. The Nrf2 phosphorylation mediated by CK2, PKC, PERK, ERK2, and JNK1 enhances the Nrf2 nuclear accumulation. In the nucleus, Nrf2 interacts with transcriptional co-activator Mafs to stabilize the ARE interaction for the transcriptional activation of antioxidant genes.

Figure 3

In AD, Aβ accumulation increases oxidative stress and blocks the Nrf2 activity by stabilizing the interaction between Keap1 and Nrf2, reducing the expression of antioxidant genes. Additionally, GSK-3β, involved in tau phosphorylation, favors Nrf2 degradation with its proteasomal degradation.

Figure 4

Chemical structure of natural compounds activating Nrf2 pathway.

Figure 5

Chemical structure of flavonoids.