Hippocampal RAGE immunoreactivity in early and advanced Alzheimer’s disease
Open accessAbstract
Microvascular accumulation and neuronal overproduction of amyloid-beta peptide (Abeta) are pathologic features of Alzheimer's disease (AD). In this study, we examined the receptor for advanced glycation endproducts (RAGE), a multi-ligand receptor found in both neurons and cerebral microvascular endothelia that binds Abeta. RAGE expression was assessed in aged controls (n = 6), patients with early AD-like pathology (n = 6), and severe, Braak V-VI AD (n = 6). Human hippocampi were stained with a specific polyclonal antibody directed against RAGE (Research Diagnostics, Flanders, NJ). Immunoreactivity was localized in both neurons and cerebral endothelial cells. Quantitative image-analyses were performed on grayscale images to assess the total surface area of endothelial RAGE immunoreaction product in cross sections of cerebral microvessels (5-20 microm). Confocal images were acquired for confirmation of RAGE immunoreactivity in both microvessels and neurons by coupling RAGE with CD-31 and neurofilament, respectively. A significant increase in endothelial RAGE immunoreactivity was found in severe Braak V-VI AD patients when compared to aged controls (p < 0.001), and when compared to patients with early AD pathology (p = 0.0125). In addition, a significant increase in endothelial RAGE immunoreactivity was witnessed when comparing aged controls having no reported AD pathology with patients having early AD-like pathology (p = 0.038). Our data suggest that microvascular RAGE levels increase in conjunction with the onset of AD, and continue to increase linearly as a function of AD pathologic severity (p < 0.0001).
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RAGE expression at the blood-brain barrier is increased in Alzheimer's disease and Alzheimer's disease models.
“Its expression at the BBB is increased in AD and AD models (134, 152, 410).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [410]
The Discussion reports increased hippocampal microvascular RAGE immunoreactivity in human AD patients and describes changes in RAGE expression at the BBB. The paper does not report an increase at the BBB in AD models; its Introduction mentions animal models only in general terms. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLRP1 levels at the blood-brain barrier are diminished in Alzheimer's disease and Alzheimer's disease models, contributing to Aβ accumulation in the brain.
“LRP1 levels at the BBB are diminished in AD and AD models contributing to A 𝛃 accumulation in the brain (137, 152, 410, 535).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [410]
The Introduction describes LRP-1 as transporting Aβ out of the brain across the blood–brain barrier, and the Discussion links altered Aβ transport to accumulation in AD. Neither section reports diminished LRP-1 levels in AD patients or AD models; the study measured RAGE, not LRP-1. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredRAGE expression is increased in Alzheimer's disease brain endothelium and mural cells.
“In contrast to LRP1, expression of RAGE, a major A 𝛃 influx receptor, is increased in AD brain endothelium and mural cells (134, 152, 410)”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [410]
The Results (Quantitative immunohistochemical analyses; page unavailable) report significantly increased RAGE immunoreactivity in hippocampal microvascular endothelium in AD compared with aged controls. The paper does not report a corresponding finding for mural cells, so that part of the claim is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRAGE expression levels are correlated with the severity of Alzheimer's disease as indicated by clinical score of the amyloid plaque or tangle.
“The levels of expression of RAGE are correlated to the severity of the disease indicated by clinical score of the amyloid plaque or tangle [45,47].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [45]
Higher levels of RAGE expression are found in neuronal, microglial, and endothelial cells in Alzheimer's disease patients compared with age-matched non-demented controls.
“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 [45]
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- Authors
- Miller, M. C., Tavares, R., Johanson, C. E., Hovanesian, V., Donahue, J. E., Gonzalez, L., Silverberg, G. D., & Stopa, E. G.
- Affiliations
- Brown University (US)
- Rhode Island Hospital (US)
- Corresponding author
- Stopa, Edward G.
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 2008-09
- Volume
- 1230
- Pages
- 273-280
- ISSN
- 0006-8993 (ISSN-L)
- PMC
- PMC2585053
- OpenAlex
- W2043890234
- Cited by
- 194
- References
- 32
- Citations by year
- 2026: 10 · 2025: 6 · 2024: 7 · 2023: 10 · 2022: 18 · 2021: 20 · 2020: 11 · 2019: 8 · 2018: 11 · 2017: 13 · 2016: 7 · 2015: 12 · 2014: 9 · 2013: 12 · 2012: 9
- FWCI
- 6.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Brown University
- National Institutes of Health
- National Institute on Aging (R01AG027910)
- 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
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- receptor for advanced glycation end products, RAGE, Alzheimer's disease, hippocampus, cerebral microvasculature, amyloid-beta, Braak staging, disease severity, endothelial cells, CD31, neurofilaments
- MeSH terms
- Receptor for Advanced Glycation End Products, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid, Female, Fluorescent Antibody Technique, Hippocampus, Humans, Image Processing, Computer-Assisted, Immunohistochemistry, Male, Microcirculation, Middle Aged, Receptors, Immunologic, Disease Progression
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