A Perspective on Nrf2 Signaling Pathway for Neuroinflammation: A Potential Therapeutic Target in Alzheimer's and Parkinson's Diseases

Abstract

Neuroinflammation plays a pivotal role in Alzheimer's disease (AD) and Parkinson's disease (PD), the leading causes of dementia. These neurological disorders are characterized by the accumulation of misfolded proteins such as amyloid-ß (Aß), tau protein and α-synuclein, contributing to mitochondrial fragmentation, oxidative stress, and neuroinflammation. Misfolded proteins activate microglia, which induces neuroinflammation, expression of pro-inflammatory cytokines and subsequently facilitates synaptic damage and neuronal loss. So far, all the proposed drugs were based on the inhibition of protein aggregation and were failed in clinical trials. Therefore, the treatment options of dementia are still a challenging issue. Thus, it is worthwhile to study alternative therapeutic strategies. In this context, there is increasing data on the pivotal role of transcription factor NF- E2 p45-related factor 2 (Nrf2) on the redox homeostasis and anti-inflammatory functions in neurodegenerative disorders. Interestingly, Nrf2 signaling pathway has shown upregulation of antioxidant genes, inhibition of microglia-mediated inflammation, and improved mitochondrial function in neurodegenerative diseases, suggesting Nrf2 activation could be a novel therapeutic approach to target pathogenesis. The present review will examine the correlation between Nrf2 signaling with neuroinflammation in AD and PD.

The Interaction of mTOR and Nrf2 in Neurogenesis and Its Implication in Neurodegenerative Diseases

“…This phenomenon is also observed in AD patients [35]. The correlation between low Nrf2 and AD can be explained due to Nrf2 playing a role in inflammation, oxidative stress, and influencing autophagy directly or indirectly [36][37][38]. Rojo [38,39].…”

Targeting NLRP3 Inflammasome With Nrf2 Inducers in Central Nervous System Disorders

“…Previous studies have reported different patterns of Nrf2 expression and its target antioxidant proteins in AD. Nrf2-ARE activation may occur in the early stage of disease and nuclear Nrf2 levels decrease in AD patients at a later stage ( 175 , 176 ). The demonstration that Nrf2 inducer SFN provides an improvement in cognitive function and amyloid pathology in PS1V97L‐Tg mice, has supported the importance of the Nrf2/ARE pathway in Alzheimer’s disease.…”

Oncogenic Pathways in Neurodegenerative Diseases

“…Nrf2 has been widely studied within the CNS [ 87 , 88 , 89 ]. Despite the different neurodegenerative diseases having diverse causes and consequences, oxidative stress is a common pathogenic mechanism in such disorders.…”

“…Loss of this function impairs the clearance of Aβ aggregates. p62 accumulates in the cytoplasm in absence of autophagy and interacts with the complex t Nrf2-Keap1 [ 89 , 97 ]. p62 releases Nrf2 from Keap1 and is translocated to the nucleus to induce the transcription of antioxidant enzymes and autophagy-related genes.…”