Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates hundreds of antioxidant genes, and is activated in response to oxidative stress. Given that many neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease and multiple sclerosis are characterised by oxidative stress, Nrf2 is commonly activated in these diseases. Evidence demonstrates that Nrf2 activity is repressed in neurons in vitro, and only cultured astrocytes respond strongly to Nrf2 inducers, leading to the interpretation that Nrf2 signalling is largely restricted to astrocytes. However, Nrf2 activity can be observed in neurons in post-mortem brain tissue and animal models of disease. Thus this interpretation may be false, and a detailed analysis of the cell type expression of Nrf2 in neurodegenerative diseases is required. This review describes the evidence for Nrf2 activation in each cell type in prominent neurodegenerative diseases and normal aging in human brain and animal models of neurodegeneration, the response to pharmacological and genetic modulation of Nrf2, and clinical trials involving Nrf2-modifying drugs.
Highlights
Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease and multiple sclerosis are characterised by the failure of specific populations of neurons, such as hippocampal neurons in Alzheimer’s disease, dopaminergic neurons in the substantia nigra in Parkinson’s disease, motor neurons in the spinal cord and motor cortex in amyotrophic lateral sclerosis, and striatal medium spiny neurons in Huntington’s disease
As TDP-43 pathology is highly prevalent in amyotrophic lateral sclerosis [167], these results suggest that nuclear factor erythroid 2-related factor 2 (Nrf2) signalling may be disrupted in this manner in the majority of amyotrophic lateral sclerosis cases
It appears that Nrf2 is activated in astrocytes in Parkinson’s disease, in astrocytes, neurons and possibly microglia in Alzheimer’s disease, and in all glial cells but not neurons in multiple sclerosis
Summary
Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease and multiple sclerosis are characterised by the failure of specific populations of neurons, such as hippocampal neurons in Alzheimer’s disease, dopaminergic neurons in the substantia nigra in Parkinson’s disease, motor neurons in the spinal cord and motor cortex in amyotrophic lateral sclerosis, and striatal medium spiny neurons in Huntington’s disease. The failure of each of these specific neuronal populations is governed by disease-dependent factors that remain unclear. This review will discuss the evidence for activation of nuclear factor erythroid 2-related factor 2 (Nrf2) in neurodegeneration, pharmacological and genetic targeting of Nrf, and in which cells Nrf is activated, focusing on Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease and multiple sclerosis. Nrf is involved in stroke, which has been recently discussed in other excellent reviews [2,3]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
