The DOI matches its Crossref record; 72 of the 72 references it cites were found in a registry or an index.
RAGE mediates Aβ accumulation in a mouse model of Alzheimer’s disease via modulation of β- and γ-secretase activity
Open accessAbstract
Receptor for Advanced Glycation End products (RAGE) has been implicated in amyloid β-peptide (Aβ)-induced perturbation relevant to the pathogenesis of Alzheimer's disease (AD). However, whether and how RAGE regulates Aβ metabolism remains largely unknown. Aβ formation arises from aberrant cleavage of amyloid pre-cursor protein (APP) by β- and γ-secretase. To investigate whether RAGE modulates β- and γ-secretase activity potentiating Aβ formation, we generated mAPP mice with genetic deletion of RAGE (mAPP/RO). These mice displayed reduced cerebral amyloid pathology, inhibited aberrant APP-Aβ metabolism by reducing β- and γ-secretases activity, and attenuated impairment of learning and memory compared with mAPP mice. Similarly, RAGE signal transduction deficient mAPP mice (mAPP/DN-RAGE) exhibited the reduction in Aβ40 and Aβ42 production and decreased β-and γ-secretase activity compared with mAPP mice. Furthermore, RAGE-deficient mAPP brain revealed suppression of activation of p38 MAP kinase and glycogen synthase kinase 3β (GSK3β). Finally, RAGE siRNA-mediated gene silencing or DN-RAGE-mediated signaling deficiency in the enriched human APP neuronal cells demonstrated suppression of activation of GSK3β, accompanied with reduction in Aβ levels and decrease in β- and γ-secretases activity. Our findings highlight that RAGE-dependent signaling pathway regulates β- and γ-secretase cleavage of APP to generate Aβ, at least in part through activation of GSK3β and p38 MAP kinase. RAGE is a potential therapeutic target to limit aberrant APP-Aβ metabolism in halting progression of AD.
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“AGEs and the receptor for advanced glycation end-products (RAGE) can play an important role in AD pathogenesis as higher levels of RAGE expression in neuronal, microglial, and endothelial cells in patients with AD compared with age-matched, non- demented controls are found [43,44,45,46].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [43]
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Molecular and genetic basis of alzheimer’s disease and emerging treatment Modalities
Varshney, H., & Siddique, Y. H. (2026) · Neurodegenerative Disease Management · doi:10.1080/17582024.2026.2739332
Elfiky, A. M., Shahy, E. M., & Mahmoud, A. A. (2026) · Physiology & Behavior · doi:10.1016/j.physbeh.2026.115532
Mishchenko, T. A., Grechukhina, A. A., Kulikov, S. S., Olajide, O. J., Mitroshina, Е. V., Krysko, D. V., & Vedunova, M. V. (2026) · Biochemistry (Moscow) · doi:10.1134/s0006297926601565
Metadata
- Authors
- Fang, F., Yu, Q., Arancio, O., Chen, D., Gore, S. S., Yan, S. S., & Yan, S. F.
- Affiliations
- University of Kansas (US)
- Columbia University (US)
- Corresponding author
- Yan, Shirley ShiDu
- Yan, Shi Fang
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-01-10
- Volume
- 27
- Issue
- 6
- Pages
- 1002-1014
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC6075512
- OpenAlex
- W2782715813
- Cited by
- 103
- References
- 72
- Citations by year
- 2026: 16 · 2025: 12 · 2024: 11 · 2023: 12 · 2022: 17 · 2021: 17 · 2020: 13 · 2019: 2 · 2018: 3
- FWCI
- 6.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Health (R37AG037319, R01AG044793, R01AG053041, R01NS089116)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- receptor for advanced glycation end products, Alzheimer's disease, amyloid-beta deposition, beta-secretase, gamma-secretase, amyloid precursor protein, GSK3β, p38 MAPK, APP processing, learning and memory impairment, therapeutic target
- MeSH terms
- Receptor for Advanced Glycation End Products, Glycogen Synthase Kinase 3 beta, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Humans, Memory, Mice, Transgenic, Neurons, Signal Transduction, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, p38 Mitogen-Activated Protein Kinases, Mice, Amyloid Precursor Protein Secretases
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