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Cited by 92Advanced Glycation End Products researchAlzheimer's disease research and treatmentsBarrier Structure and Function Studies

Role of Aβ-receptor for advanced glycation endproducts interaction in oxidative stress and cytosolic phospholipase A2 activation in astrocytes and cerebral endothelial cells

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Askarova, S., Yang, X., Sheng, W., Sun, G.Y., Lee, J.C.-M.·2011·Neuroscience
DOI 10.1016/j.neuroscience.2011.09.038PMC PMC3237818
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Abstract

Blood-brain barrier (BBB) dysfunctions have been implicated in the progression of Alzheimer's disease. Cerebral endothelial cells (CECs) and astrocytes are the main cell components of the BBB. Although amyloid-β oligomers (Aβ₄₂) have been reported to mediate oxidative damage to the CECs and astrocytes and trigger the downstream mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway, the cell surface binding site for Aβ₄₂ and exact sequence of these events have yet to be elucidated. In this study, the receptor for advanced glycation endproducts (RAGE) was postulated to function as a signal transducing cell surface receptor for Aβ₄₂ to induce reactive oxygen species (ROS) generation from NADPH oxidase and trigger downstream pathways for the phosphorylation of extracellular signal-regulated kinases (ERK1/2) and cytosolic phospholipase A₂ (cPLA₂). We found that Aβ₄₂ competed with the anti-RAGE antibody (Ab(RAGE)) to bind to RAGE on the surfaces of CECs and primary astrocytes. In addition, Ab(RAGE) abrogate Aβ₄₂-induced ROS production and the colocalization between the cytosolic (p47-phox) and membrane (gp91-phox) subunits of NADPH oxidase in both cell types. Ab(RAGE) as well as NADPH oxidase inhibitor and ROS scavenger suppressed Aβ₄₂-induced ERK1/2 and cPLA₂ phosphorylation in CECs. At the same time, only Ab(RAGE), but neither NADPH oxidase inhibitor nor ROS scavenger, inhibited the ERK1/2 pathway and cPLA₂ phosphorylation in primary astrocytes. Therefore, this study demonstrates that NADPH oxidase complex assembly and ROS production are not required for Aβ₄₂ binding to RAGE at astrocytic surface leading to sequential phosphorylation of ERK1/2 and cPLA₂, and suggests the presence of two different RAGE-dependent downstream pathways in the CECs and astrocytes.

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  • Binding of Aβ with endothelial RAGE receptor induces oxidative stress via NOX and ROS, ultimately inducing inflammation and impairing tight junctions, leading to loss of BBB integrity and interruption of cerebral blood flow.

    “Binding of Aβ with endothelial RAGE receptor also induced oxidative stress, as indicated by improved NADPH oxidase (NOX) and increased the generation of ROS (primarily peroxynitrite), which ultimately induced inflammation and impaired tight junctions, leading to loss of BBB integrity481,482 and interruption of cerebral blood flow.483”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [481]

    The Results (§3.1–3.2) and Discussion (§4; page unavailable) support Aβ42 binding to RAGE on cerebral endothelial cells and inducing NADPH-oxidase-dependent ROS production. The Introduction (§1) links Aβ-induced oxidative stress to neurovascular inflammation, but the paper does not establish that these ROS are primarily peroxynitrite or that this pathway impairs tight junctions, causes loss of BBB integrity, or interrupts cerebral blood flow. The Discussion reports reduced cerebral blood flow in AD as background, not as a measured consequence of this pathway. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Astrocytes may play an important role in the transport of Aβ into or out of the CNS through the astrocyte-vasculature interface.

    “Moreover, astrocytes may play an important role in the transport of Aβ into or out of the CNS through this important interface (63).”

    From Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice (2013) · cites this paper as [63]

    The Introduction (page not available) says Aβ binding to RAGE regulates transport across the blood–brain barrier, and the paper identifies astrocytes as a component of that barrier. It does not say that astrocytes themselves transport Aβ into or out of the CNS through the astrocyte–vasculature interface. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 53

  1. Abramov AY Duchen MR The role of an astrocytic NADPH oxidase in the neurotoxicity of amyloid beta peptides Philosophical Transactions of the Royal Society B: Biological Sciences 2005 360 2309 2314 PMC1569597 16321801
  2. Arancio O Zhang HP Chen X Lin C Trinchese F Puzzo D Liu S Hegde A Yan SF Stern A Luddy JS Lue L-F Walker DG Roher A Buttini M Mucke L Li W Schmidt AM Kindy M Hyslop PA Stern DM Du Yan SS RAGE potentiates A[beta]-induced perturbation of neuronal function in transgenic mice EMBO J 2004 23 4096 4105 15457210 PMC524347
  3. Babior BM NADPH Oxidase: An Update Blood 1999 93 1464 1476 10029572
  4. Bailey TL Rivara CB Rocher AB Hof PR The nature and effects of cortical microvascular pathology in aging and Alzheimer's disease Neurological Research 2004 26 573 578 15265277
  5. Behl C Davis JB Lesley R Schubert D Hydrogen peroxide mediates amyloid beta protein toxicity Cell 1994 77 817 827 8004671
  6. Behl C Holsboer F Oxidative stress in the pathogenesis of Alzheimer's disease and antioxidant neuroprotection Fortschr Neurol Psychiatr 1998 66 113 121 9565761
  7. Bell R Zlokovic B Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer's disease Acta Neuropathologica 2009 118 103 113 19319544 PMC2853006
  8. Berzin TM Zipser BD Rafii MS Kuo--Leblanc V Yancopoulos GD Glass DJ Fallon JR Stopa EG Agrin and microvascular damage in Alzheimer's disease Neurobiology of Aging 2000 21 349 355 10867220
  9. Borroni B Akkawi N Martini G Colciaghi F Prometti P Rozzini L Di Luca M Lenzi GL Romanelli G Caimi L Padovani A Microvascular damage and platelet abnormalities in early Alzheimer's disease Journal of the Neurological Sciences 2002 203–204 189 193 12417382
  10. Chaney MO Stine WB Kokjohn TA Kuo Y-M Esh C Rahman A Luehrs DC Schmidt AM Stern D Yan SD Roher AE RAGE and amyloid beta interactions: Atomic force microscopy and molecular modeling Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2005 1741 199 205 15882940
  11. Cherny VV Henderson LM Xu W Thomas LL DeCoursey TE Activation of NADPH oxidase-related proton and electron currents in human eosinophils by arachidonic acid The Journal of Physiology 2001 535 783 794 11559775 PMC2278825
  12. Cini M Moretti A Studies on lipid peroxidation and protein oxidation in the aging brain Neurobiol Aging 1995 16 53 57 7723936
  13. de la Torre JC How do heart disease and stroke become risk factors for Alzheimer's disease? Neurological Research 2006 28 637 644 16945216
  14. Deane R Zlokovic BV Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease Curr Alzheimer Res 2007 4 191 197 17430246
  15. Dineley KT Westerman M Bui D Bell K Ashe KH Sweatt JD {beta}-Amyloid Activates the Mitogen-Activated Protein Kinase Cascade via Hippocampal {alpha}7 Nicotinic Acetylcholine Receptors: In Vitro and In Vivo Mechanisms Related to Alzheimer's Disease J Neurosci 2001 21 4125 4133 11404397 PMC6762764
  16. Emmanuelle MB Michal T Robert JM Bernhard H Amyloid β-Peptide Induces Cell Monolayer Albumin Permeability, Impairs Glucose Transport, and Induces Apoptosis in Vascular Endothelial Cells Journal of Neurochemistry 1997 68 1870 1881 9109512
  17. Ervin JF Pannell C Szymanski M Welsh-Bohmer K Schmechel DE Hulette CM Vascular Smooth Muscle Actin Is Reduced in Alzheimer Disease Brain: A Quantitative Analysis Journal of Neuropathology & Experimental Neurology 2004 63 735 741 15290898
  18. Giri R Shen Y Stins M Du Yan S Schmidt AM Stern D Kim KS Zlokovic B Kalra VK Beta-amyloid-induced migration of monocytes across human brain endothelial cells involves RAGE and PECAM-1 Am J Physiol Cell Physiol 2000 279 C1772 1781 11078691
  19. Girouard H Iadecola C Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease J Appl Physiol 2006 100 328 335 16357086
  20. Heneka MT O'Banion MK Inflammatory processes in Alzheimer's disease J Neuroimmunol 2007 184 69 91 17222916
  21. Heumuller S Wind S Barbosa-Sicard E Schmidt HHHW Busse R Schroder K Brandes RP Apocynin Is Not an Inhibitor of Vascular NADPH Oxidases but an Antioxidant Hypertension 2008 51 211 217 18086956
  22. Hicks JB Lai Y Sheng W Yang X Zhu D Sun GY Lee JC Amyloid-beta peptide induces temporal membrane biphasic changes in astrocytes through cytosolic phospholipase A2 Biochim Biophys Acta 2008 1778 2512 2519 18725190 PMC2592609
  23. Hofman A Ott A Breteler MMB Bots ML Slooter AJC van Harskamp F van Duijn CN Van Broeckhoven C Grobbee DE Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study The Lancet 1997 349 151 154 9111537
  24. Hsu M-J Hsu CY Chen B-C Chen M-C Ou G Lin C-H Apoptosis Signal-Regulating Kinase 1 in Amyloid -beta- Peptide-Induced Cerebral Endothelial Cell Apoptosis J Neurosci 2007 27 5719 5729 17522316 PMC6672775
  25. Iadecola C Cerebrovascular effects of amyloid-beta peptides: mechanisms and implications for Alzheimer's dementia Cell Mol Neurobiol 2003 23 681 689 14514024 PMC11530195
  26. Kalaria RN Pax AB Increased collagen content of cerebral microvessels in Alzheimer's disease Brain Research 1995 705 349 352 8821769
  27. Levy R The role of cytosolic phospholipase A2-alfa in regulation of phagocytic functions Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 2006 1761 1323 1334 17046321
  28. Luc B Patrick RHOF Andre D Brain Microvascular Changes in Alzheimer's Disease and Other Dementias Annals of the New York Academy of Sciences 1997 826 7 24 9329677
  29. Lue L-F Walker DG Brachova L Beach TG Rogers J Schmidt AM Stern DM Yan SD Involvement of Microglial Receptor for Advanced Glycation Endproducts (RAGE) in Alzheimer's Disease: Identification of a Cellular Activation Mechanism Experimental Neurology 2001 171 29 45 11520119
  30. McDonald DR Bamberger ME Combs CK Landreth GE beta -Amyloid Fibrils Activate Parallel Mitogen-Activated Protein Kinase Pathways in Microglia and THP1 Monocytes J Neurosci 1998 18 4451 4460 9614222 PMC6792680
  31. Mecocci P MacGarvey U Beal MF Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease Ann Neurol 1994 36 747 751 7979220
  32. Moses GS Jensen MD Lue LF Walker DG Sun AY Simonyi A Sun GY Secretory PLA2-IIA: a new inflammatory factor for Alzheimer's disease J Neuroinflammation 2006 3 28 17026770 PMC1613236
  33. Murakami M Kudo I Phospholipase A2 J Biochem 2002 131 285 292 11872155
  34. Origlia N Arancio O Domenici L Yan SS MAPK, OI-amyloid and synaptic dysfunction: the role of RAGE Expert Review of Neurotherapeutics 2009 9 1635 1645 19903023 PMC8965749
  35. Qing L Jiu-Hong K Rong-Liang Z NADPH oxidase produces reactive oxygen species and maintains survival of rat astrocytes Cell Biochemistry and Function 2005 23 93 100 15386527
  36. Riganti C Costamagna C Bosia A Ghigo D The NADPH oxidase inhibitor apocynin (acetovanillone) induces oxidative stress Toxicology and Applied Pharmacology 2006 212 179 187 16120450
  37. Shelat P B. Chalimoniuk M Wang J-H Strosznajder J B. Lee J C. Sun A Y. Simonyi A Sun G Y. Amyloid beta peptide and NMDA induce ROS from NADPH oxidase and AA release from cytosolic phospholipase A<sub>2</sub> in cortical neurons Journal of Neurochemistry 2008 106 45 55 18346200
  38. Simonian NA Coyle JT Oxidative stress in neurodegenerative diseases Annu Rev Pharmacol Toxicol 1996 36 83 106 8725383
  39. Smith CD Carney JM Starke-Reed PE Oliver CN Stadtman ER Floyd RA Markesbery WR Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease Proc Natl Acad Sci U S A 1991 88 10540 10543 1683703 PMC52964
  40. Stephenson D Rash K Smalstig B Roberts E Johnstone E Sharp J Panetta J Little S Kramer R Clemens J Cytosolic phospholipase A2 is induced in reactive glia following different forms of neurodegeneration Glia 1999 27 110 128 10417811
  41. Stephenson DT Lemere CA Selkoe DJ Clemens JA Cytosolic phospholipase A2 (cPLA2) immunoreactivity is elevated in Alzheimer's disease brain Neurobiol Dis 1996 3 51 63 9173912
  42. Sun GY Horrocks LA Farooqui AA The roles of NADPH oxidase and phospholipases A<sub>2</sub> in oxidative and inflammatory responses in neurodegenerative diseases Journal of Neurochemistry 2007 103 1 16 17561938
  43. Sun GY Xu J Jensen MD Simonyi A Phospholipase A2 in the central nervous system: implications for neurodegenerative diseases J Lipid Res 2004 45 205 213 14657205
  44. Tan J Town T Suo Z Wu Y Song S Kundtz A Kroeger J Humphrey J Crawford F Mullan M Induction of CD40 on human endothelial cells by Alzheimer's [beta]-amyloid peptides Brain Research Bulletin 1999 50 143 148 10535333
  45. Vukic V Callaghan D Walker D Lue L-F Liu QY Couraud P-O Romero IA Weksler B Stanimirovic DB Zhang W Expression of inflammatory genes induced by beta-amyloid peptides in human brain endothelial cells and in Alzheimer's brain is mediated by the JNK-AP1 signaling pathway Neurobiology of Disease 2009 34 95 106 19162185 PMC2720310
  46. Wautier M-P Chappey O Corda S Stern DM Schmidt AM Wautier J-L Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE Am J Physiol Endocrinol Metab 2001 280 E685 694 11287350
  47. Xu J Chen S Ku G Ahmed SH Xu J Chen H Hsu CY Amyloid beta Peptide-Induced Cerebral Endothelial Cell Death Involves Mitochondrial Dysfunction and Caspase Activation J Cereb Blood Flow Metab 2001 21 702 710 11488539
  48. Yin KJ Lee JM Chen SD Xu J Hsu CY Amyloid-beta Induces Smac Release via AP-1/Bim Activation in Cerebral Endothelial Cells J Neurosci 2002 22 9764 9770 12427831 PMC6757851
  49. Young KF Pasternak SH Rylett RJ Oligomeric aggregates of amyloid [beta] peptide 1–42 activate ERK/MAPK in SH-SY5Y cells via the [alpha]7 nicotinic receptor Neurochemistry International 2009 55 796 801 19666073
  50. Zanetti M d'Uscio LV Peterson TE Katusic ZS O'Brien T Analysis of Superoxide Anion Production in Tissue Hypertension 2005 65 72 16028676
  51. Zhu D Hu C Sheng W Tan KS Haidekker MA Sun AY Sun GY Lee JC-M NAD(P)H oxidase-mediated reactive oxygen species production alters astrocyte membrane molecular order via phospholipase A2 Biochem J 2009 421 201 210 19392662
  52. Zhu D Lai Y Shelat PB Hu C Sun GY Lee JCM Phospholipases A2 Mediate Amyloid-beta Peptide-Induced Mitochondrial Dysfunction J Neurosci 2006 26 11111 11119 17065451 PMC6674660
  53. Zlokovic BV New therapeutic targets in the neurovascular pathway in Alzheimer's disease Neurotherapeutics 2008 5 409 414 18625452 PMC2536515

Cited by

Sorted by citations

Authors
Askarova, S., Yang, X., Sheng, W., Sun, G. Y., & Lee, J. C.-M.
Affiliations
University of Missouri (US)
Corresponding author
Lee, J.C.-M.
ORCID
Venue
Neuroscience
Publisher
Elsevier BV
Published
2011-12
Volume
199
Pages
375-385
ISSN
0306-4522 (ISSN-L)
DOI
10.1016/j.neuroscience.2011.09.038
PMC
PMC3237818
OpenAlex
W2076632992
Cited by
92
References
9
Citations by year
2026: 4 · 2025: 4 · 2024: 3 · 2023: 6 · 2022: 6 · 2021: 5 · 2020: 11 · 2019: 4 · 2018: 5 · 2017: 3 · 2016: 6 · 2015: 6 · 2014: 13 · 2013: 10 · 2012: 6
FWCI
5.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Nazarbayev University Repository (Nazarbayev University) (submittedVersion, cc-by-nc-sa)
Funders
  • Alzheimer's Association (NIRG-06-24448)
  • National Institutes of Health (1P01 AG18357, R21AG032579, R21NS052385)
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 › Barrier Structure and Function Studies
Keywords
amyloid-beta oligomers, receptor for advanced glycation end products, RAGE, NADPH oxidase, reactive oxygen species, cytosolic phospholipase A2, ERK1/2 phosphorylation, astrocytes, brain endothelial cells, blood-brain barrier, Alzheimer's disease, MAPK/ERK pathway, oxidative stress, gp91phox, p47phox
MeSH terms
Receptor for Advanced Glycation End Products, Animals, Astrocytes, Blood-Brain Barrier, Brain, Cell Line, Enzyme Activation, Fluorescent Antibody Technique, Microscopy, Fluorescence, Protein Binding, Receptors, Immunologic, Blotting, Western, Signal Transduction, Amyloid beta-Peptides, Reactive Oxygen Species, Oxidative Stress, Microscopy, Confocal, NADPH Oxidases, Endothelial Cells, Mice, Phospholipases A2, Cytosolic

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