Can Co-Activation of Nrf2 and Neurotrophic Signaling Pathway Slow Alzheimer’s Disease?

Abstract

Alzheimer’s disease (AD) is a multifaceted disease that is hard to treat by single-modal treatment. AD starts with amyloid peptides, mitochondrial dysfunction, and oxidative stress and later is accompanied with chronic endoplasmic reticulum (ER) stress and autophagy dysfunction, resulting in more complicated pathogenesis. Currently, few treatments can modify the complicated pathogenic progress of AD. Compared to the treatment with exogenous antioxidants, the activation of global antioxidant defense system via Nrf2 looks more promising in attenuating oxidative stress in AD brains. Accompanying the activation of the Nrf2-mediated antioxidant defense system that reduce the AD-causative factor, oxidative stress, it is also necessary to activate the neurotrophic signaling pathway that replaces damaged organelles and molecules with new ones. Thus, the dual actions to activate both the Nrf2 antioxidant system and neurotrophic signaling pathway are expected to provide a better strategy to modify AD pathogenesis. Here, we review the current understanding of AD pathogenesis and neuronal defense systems and discuss a possible way to co-activate the Nrf2 antioxidant system and neurotrophic signaling pathway with the hope of helping to find a better strategy to slow AD.

Mini-GAGR, an intranasally applied polysaccharide, activates the neuronal Nrf2-mediated antioxidant defense system

“…The neurotrophic effect of midi-GAGR appears to partly contribute to its neuroprotective effect ( 28 ), although it might not be sufficient enough to offer neuronal protection against oxidative stress. Given that antioxidant enzymes are the major endogenous defense system to scavenge free reactive radicals ( 1 ), it is possible that antioxidant enzymes might be increased by the low-acyl gellan gum cleavage product, mini-GAGR. To examine this possibility, we tested the effect of mini-GAGR on the protein levels of several major antioxidant enzymes in mouse embryonic cortical neurons (E17, DIV11–14).…”

“…Because Nrf2 is the major transcriptional factor for the expression of antioxidant enzymes ( 1 ), it is possible that mini-GAGR, which increases antioxidant enzymes, activates Nrf2 in mouse cortical neurons. First, we examined whether mini-GAGR induced the nuclear translocation of Nrf2 in mouse cortical neurons (E17, DIV11–14).…”

“…Oxidative stress is thought to be a major trigger of AD, as we reviewed recently ( 1 ). Usually, aging gradually reduces endogenous antioxidant capacity, causing surrender to overwhelming oxidative species.…”

Spirulina maxima Extract Ameliorates Learning and Memory Impairments via Inhibiting GSK-3β Phosphorylation Induced by Intracerebroventricular Injection of Amyloid-β 1–42 in Mice

“…Recently, it was shown that stimulation of the BDNF/PI3K/Akt signaling pathway leads to the inhibition of GSK-3β phosphorylation [ 19 ]. Moreover, activation of the BDNF/PI3K/Akt signaling pathway suppresses oxidative stress caused by Aβ peptides [ 43 ]. Thus, we investigated the BDNF/PI3K/Akt signaling pathway to further examine the association between BDNF and oxidative stress induced by Aβ peptides.…”

The neuroprotective activities of natural products through the Nrf2 upregulation

“…Oxidative stress is one of the important characteristics of AD-resulting brain damage, and oxidative stress can be altered by the Nrf2-ARE antioxidant pathway. This pathway can be activated by a number of natural products especially the flavonoids and nonflavonoid polyphenols (Murphy & Park, 2017). The essential oil of Su He Xiang Wan (SHXW), a traditional Chinese medicine, has been showed to suppress Aβ-induced apoptosis and ROS production through upregulation of Nrf2 and HO-1 expression in SH-SY5Y cells.…”