Keap1 is localized in neuronal and glial cytoplasmic inclusions in various neurodegenerative diseases
Abstract
Oxidative stress has been proposed as a potential mechanism for neurodegenerative diseases, such as Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). In response to oxidative stress, the levels of numerous cytoprotective products are increased via alteration of the Kelch-like ECH-associated protein 1 (Keap1) and NF-E2-related factor 2 (Nrf2) system. One of the Nrf2 targets, p62, has been known to be incorporated into a wide spectrum of cytoplasmic inclusions in neurodegenerative diseases and interact with Keap1. However, it remains unclear whether Keap1 is associated with the pathogenesis of neurodegenerative diseases. In this study, we investigated the relationship between p62 and Keap1 in the brains of patients with AD, PD, dementia with Lewy bodies (DLB), and ALS. Biochemical analyses showed that p62 and Keap1 interacted with each other in AD and DLB brains and were extracted into similar detergent-soluble and -insoluble fractions. Pathologic examination demonstrated that anti-Keap1 antibodies immunostained Lewy bodies in PD and DLB, neurofibrillary tangles in AD, and skeinlike inclusions in ALS. Further analysis showed that the levels of common Nrf2 target genes were increased in AD compared with those in controls. However, there were no statistical significances in the levels of Nrf2 target genes in DLB relative to controls. Our pathologic and biochemical results suggest a molecular basis for stress response to be involved in the formation of cytoplasmic inclusions observed in several neurodegenerative diseases.
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Ho-1 and NQO1 are upregulated in AD patients.
“Ho-1 and NQO1 are upregulated in AD patients [22,23]”
From Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice (2019) · cites this paper as [22]
Numerous other studies demonstrate both an increase and decrease in ARE gene expression in AD brain tissue, with an initial heightened antioxidant response due to oxidative stress followed by eventual exhaustion with decrease of ARE pathway signaling.
“Numerous other studies demonstrate both an increase and decrease in ARE gene expression in AD brain tissue, citing an initial heightened antioxidant response due to oxidative stress [22,86,87], followed by its eventual exhaustion with the decrease of ARE pathway signaling [88].”
From Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice (2019) · cites this paper as [22]
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- Authors
- Tanji, K., Maruyama, A., Odagiri, S., Mori, F., Itoh, K., Kakita, A., Takahashi, H., & Wakabayashi, K.
- Affiliations
- Hirosaki University (JP)
- Brain Research Institute, Niigata University (JP)
- Corresponding author
- Tanji, Kunikazu
- ORCID
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-01
- Volume
- 72
- Issue
- 1
- Pages
- 18-28
- ISSN
- 0022-3069 (ISSN-L)
- 1554-6578
- OpenAlex
- W2009889649
- Cited by
- 80
- References
- 51
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 12 · 2020: 3 · 2019: 10 · 2018: 2 · 2017: 9 · 2016: 7 · 2015: 5 · 2014: 6 · 2013: 7
- FWCI
- 2.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (23500425, 25860202, 23500424, 24659122, 24300131, 24700363)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- Keap1, p62, Nrf2, neurodegenerative diseases, cytoplasmic inclusions, oxidative stress, Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, Lewy bodies, neurofibrillary tangles, Nrf2 target genes, protein-protein interaction
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Aged, Aged, 80 and over, Brain, Brain Chemistry, Inclusion Bodies, Female, Humans, Male, Middle Aged, Neuroglia, Neurons, Protein Binding, Neurodegenerative Diseases, Intracellular Signaling Peptides and Proteins
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