Every Cloud Has a Silver Lining: Proneurogenic Effects of Aβ Oligomers and HMGB-1 via Activation of the RAGE-NF-κB Axis
Abstract
BACKGROUND & OBJECTIVE: Since its initial discovery, current understanding on the functional role of the Receptor for Advanced Glycation End-products (RAGE) in physiology and in pathology has impressively grown, especially in consideration of its large ligand repertoire (AGEs, HMGB-1, β amyloid, S100B/S100A12) and its potential involvement in the pathophysiology of several chronic human disorders. Downstream RAGE engagement by its ligands, NF-κB signaling activation has been demonstrated in several cell phenotypes, including neurons and glia. Based on the observation that in Alzheimer's Disease (AD) brain expression of RAGE and its ligands is upregulated and that RAGE/NF-κB axis activation can trigger an autoregulatory loop which further amplifies neuroinflammation and neurodegeneration, this signaling pathway has been hypothesized to greatly contribute to AD pathophysiology. Herein we review the vast array of information supporting a detrimental role of RAGE/NF-κB axis activation in AD brain and discuss those data in the context of recent findings obtained in our laboratory pointing to an unexpected effect elicited by this signaling pathway which may rather contribute to reparative mechanisms in AD, namely positive modulation of adult neurogenesis. Interestingly, the proneurogenic effect resulting from RAGE/NF-κB axis activation could be induced by molecules which are commonly considered as mediators of toxicity, like Aβ oligomers and HMGB-1. CONCLUSION: Altogether, despite a large set of data suggesting that RAGE may represent an interesting target for the pharmacological treatment of AD, the complex functional roles of the receptor would require the use of molecules able to counteract RAGE negative effects without altering the positive ones such as the promotion of adult neurogenesis.
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Aβ can bind RAGEs to activate NF-κB and other signal transducer and activator of transcription pathways, leading to neuronal cell death and neurodegeneration.
“Aβ can also bind RAGEs to activate the NF-κB, and other signal transducers and activators of transcription pathways, leading to neuronal cell death and neurodegeneration [49].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [49]
HMGB1 and Aβ can bind RAGEs to activate the NF-κB, ERK1/2, p38, JNK, PI3K, JAK/STAT pathways, leading to neuronal cell death and neurodegeneration.
“In addition to AGEs and AGE adducts, HMGB1 and Aβ can bind RAGEs to activate the NF-κB, ERK1/2, p38, JNK, PI3K, Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways, leading to neuronal cell death and neurodegeneration112.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [112]
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- Authors
- Bortolotto, V., & Grilli, M.
- Affiliations
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- Corresponding author
- Grilli, Mariagrazia
- Venue
- CNS & Neurological Disorders - Drug Targets
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2018-03-13
- Volume
- 16
- Issue
- 10
- Pages
- 1066-1079
- ISSN
- 1568-007X (ISSN-L)
- 1871-5273
- OpenAlex
- W2491610014
- Cited by
- 35
- References
- 0
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2022: 2 · 2021: 8 · 2020: 7 · 2019: 1 · 2018: 2 · 2017: 5
- FWCI
- 2.63
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- CNS & Neurological Disorders - Drug Targets (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, receptor for advanced glycation end products, RAGE, NF-κB signaling, amyloid-beta oligomers, HMGB1, adult neurogenesis, neuroinflammation, neurodegeneration, RAGE ligands
- MeSH terms
- Receptor for Advanced Glycation End Products, Alzheimer Disease, Animals, Humans, Signal Transduction, Amyloid beta-Peptides, NF-kappa B, HMGB1 Protein, Neurogenesis
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