CoChat
Sign Up
Cited by 48Barrier Structure and Function StudiesAlzheimer's disease research and treatmentsDrug Transport and Resistance Mechanisms

Endothelial dysfunctions in blood-brain barrier breakdown in alzheimer's disease: from mechanisms to potential therapies

Open access
Yue, Qian, Leng, Xinyue, Xie, Ningqing, Zhang, Zaijun, Yang, Deguang, Hoi, Maggie Pui Man·2024·CNS Neuroscience & Therapeutics
DOI 10.1111/cns.70079PMC PMC11567945
Open this paper in CoChat — free account

Abstract

Recent research has shown the presence of blood–brain barrier (BBB) breakdown in Alzheimer's disease (AD). BBB is a dynamic interface consisting of a continuous monolayer of brain endothelial cells (BECs) enveloped by pericytes and astrocytes. The restricted permeability of BBB strictly controls the exchange of substances between blood and brain parenchyma, which is crucial for brain homeostasis by excluding blood‐derived detrimental factors and pumping out brain‐derived toxic molecules. BBB breakdown in AD is featured as a series of BEC pathologies such as increased paracellular permeability, abnormal levels and functions of transporters, and inflammatory or oxidative profile, which may disturb the substance transportation across BBB, thereafter induce CNS disorders such as hypometabolism, Aβ accumulation, and neuroinflammation, eventually aggravate cognitive decline. Therefore, it seems important to protect BEC properties for BBB maintenance and neuroprotection. In this review, we thoroughly summarized the pathological alterations of BEC properties reported in AD patients and numerous AD models, including paracellular permeability, influx and efflux transporters, and inflammatory and oxidative profiles, and probably associated underlying mechanisms. Then we reviewed current therapeutic agents that are effective in ameliorating a series of BEC pathologies, and ultimately protecting BBB integrity and cognitive functions. Regarding the current drug development for AD proceeds extremely hard, this review aims to discuss the therapeutic potentials of targeting BEC pathologies and BBB maintenance for AD treatment, therefore expecting to shed a light on the future AD drug development by targeting BEC pathologies and BBB protection.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1111/cns.70079

Cites

15 of 15 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Enhanced endothelial integrity may limit paracellular permeability to inflammatory mediators, preserve regulated transport processes across the barrier, and contribute to a more stable neurovascular microenvironment, particularly in the context of AD-associated vascular dysfunction.

    “Beyond structural stabilization of the BBB, enhanced endothelial integrity may limit paracellular permeability to inflammatory mediators, preserve regulated transport processes across the barrier, and contribute to a more stable neurovascular microenvironment, particularly in the context of AD-associated vascular dysfunction (Yue et al., 2024).”

    From APOE3-Christchurch variant enhances neurovascular support functions of iPSC-derived mesenchymal stromal cells (2026) · cites this paper as Yue et al., 2024

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 262

  1. [1]S. Ahmad, S. A. Khan, A. Kindelin, et al., “ Acetyl‐11‐Keto‐β‐Boswellic Acid (AKBA) Attenuates Oxidative Stress, Inflammation, Complement Activation and Cell Death in Brain Endothelial Cells Following OGD/Reperfusion,” Neuromolecular Medicine 21 (2019a): 505– 516. 31515728
  2. [3]A. Rihani, B. Sweilem, L. I. Darakjian, and A. Kaddoumi, “ Oleocanthal‐Rich Extra‐Virgin Olive Oil Restores the Blood–Brain Barrier Function Through NLRP3 Inflammasome Inhibition Simultaneously With Autophagy Induction in TgSwDI Mice,” ACS Chemical Neuroscience 10 (2019): 3543– 3554. 31244050 PMC6703911
  3. [4]A. Narasimhulu, C. M. Chandrakala, D. Bhardwaj, K. Y. Burge, and S. Parthasarathy, “ Alzheimer's Disease Markers in Aged ApoE‐PON1 Deficient Mice,” Journal of Alzheimer's Disease 67 (2019): 1353– 1365. 30714958
  4. [5]V. C. Anderson, I. J. Tagge, X. Li, et al., “ Observation of Reduced Homeostatic Metabolic Activity and/or Coupling in White Matter Aging,” Journal of Neuroimaging 30 (2020): 658– 665. 32558031 PMC7529981
  5. [6]A. T. Argaw, L. Asp, J. Zhang, et al., “ Astrocyte‐Derived VEGF‐A Drives Blood‐Brain Barrier Disruption in CNS Inflammatory Disease,” Journal of Clinical Investigation 122 (2012): 2454– 2468. 22653056 PMC3386814
  6. [7]A. T. Argaw, Y. Zhang, B. J. Snyder, et al., “ IL‐1β Regulates Blood‐Brain Barrier Permeability via Reactivation of the Hypoxia‐Angiogenesis Program,” Journal of Immunology 177 (2006): 5574– 5584. 17015745
  7. [8]S. E. Arnold, Z. Arvanitakis, S. L. Macauley‐Rambach, et al., “ Brain Insulin Resistance in Type 2 Diabetes and Alzheimer Disease: Concepts and Conundrums,” Nature Reviews Neurology 14 (2018): 168– 181. 29377010 PMC6098968
  8. [9]Z. Arvanitakis, A. W. Capuano, S. E. Leurgans, D. A. Bennett, and J. A. Schneider, “ Relation of Cerebral Vessel Disease to Alzheimer's Disease Dementia and Cognitive Function in Elderly People: A Cross‐Sectional Study,” Lancet Neurology 15 (2016): 934– 943. 27312738 PMC4969105
  9. [10]Z. Arvanitakis, H.‐Y. Wang, A. W. Capuano, et al., “ Brain Insulin Signaling, Alzheimer Disease Pathology, and Cognitive Function,” Annals of Neurology 88 (2020): 513– 525. 32557841 PMC7722192
  10. [11]S. J. Baloyannis and I. S. Baloyannis, “ The Vascular Factor in Alzheimer's Disease: A Study in Golgi Technique and Electron Microscopy,” Journal of the Neurological Sciences 322 (2012): 117– 121. 22857991
  11. [13]M. Barrand, “ Beta Amyloid Effects on Expression of Multidrug Efflux Transporters in Brain Endothelial Cells,” Brain research 1418 (2011): 1– 11. 21920506
  12. [14]Y. S. Batarseh, S. S. Bharate, V. Kumar, et al., “ Crocus Sativus Extract Tightens the Blood‐Brain Barrier, Reduces Amyloid β Load and Related Toxicity in 5XFAD Mice,” ACS Chemical Neuroscience 8 (2017): 1756– 1766. 28471166 PMC5559303
  13. [15]R. P. Bazinet and S. Layé, “ Polyunsaturated Fatty Acids and Their Metabolites in Brain Function and Disease,” Nature Reviews Neuroscience 15 (2014): 771– 785. 25387473
  14. [17]R. S. Beard, J. J. Reynolds, and S. E. Bearden, “ Metabotropic Glutamate Receptor 5 Mediates Phosphorylation of Vascular Endothelial Cadherin and Nuclear Localization of β‐Catenin in Response to Homocysteine,” Vascular Pharmacology 56 (2012): 159– 167. 22285407 PMC3304005
  15. [18]R. S. Beard, R. J. Haines, K. Y. Wu, et al., “ Non‐muscle Myosin Light Chain Kinase Is Required for β‐Catenin/FoxO1‐Dependent Downregulation of Claudin‐5 in Interleukin‐1β‐Mediated Brain Endothelial Cell Barrier Dysfunction,” Journal of Cell Science 127 (2014): 144550. PMC4074294 24522189
  16. [19]T. Behl, I. Kaur, A. Sehgal, M. Arun Kumar, S. Uddin, and S. Bungau, “ The Interplay of ABC Transporters in Aβ Translocation and Cholesterol Metabolism: Implicating Their Roles in Alzheimer's Disease,” Molecular Neurobiology 58 (2021): 1564– 1582. 33215389
  17. [21]R. D. Bell and B. V. Zlokovic, “ Neurovascular Mechanisms and Blood–Brain Barrier Disorder in Alzheimer's Disease,” Acta Neuropathologica 118 (2009): 103– 113. 19319544 PMC2853006
  18. [22]A. Ben‐Zvi, B. Lacoste, E. Kur, et al., “ Mfsd2a Is Critical for the Formation and Function of the Blood–Brain Barrier,” Nature 509 (2014): 507– 511. 24828040 PMC4134871
  19. [23]Z. Bian, T. Yamashita, X. Shi, et al., “ Accelerated Accumulation of Fibrinogen Peptide Chains With Aβ Deposition in Alzheimer's Disease (AD) Mice and Human AD Brains,” Brain Research 1767 (2021): 147569. 34197775
  20. [24]A. Boehm‐Cagan, R. Bar, O. Liraz, J. K. Bielicki, J. O. Johansson, and D. M. Michaelson, “ ABCA1 Agonist Reverses the ApoE4‐Driven Cognitive and Brain Pathologies,” Journal of Alzheimer's Disease 54 (2016): 1219– 1233. 27567858
  21. [25]E. Brook, J. Mamo, R. Wong, et al., “ Blood‐Brain Barrier Disturbances in Diabetes‐Associated Dementia: Therapeutic Potential for Cannabinoids,” Pharmacological Research 141 (2019): 291– 297. 30616019
  22. [26]Y. Cai, Y. Lu, F. Niu, K. Liao, and S. Buch, “ Role of Sigma‐1 Receptor in Cocaine Abuse and Neurodegenerative Disease,” Sigma Receptors: Their Role in Disease and as Therapeutic Targets 964 (2017): 163– 175. 28315271
  23. [27]Y. Cao, F. Wang, Y. Wang, and J. Long, “ Agomelatine Prevents Macrophage Infiltration and Brain Endothelial Cell Damage in a Stroke Mouse Model,” Aging (Albany NY) 13 (2021): 13548– 13559. 33839700 PMC8202857
  24. [29]J. M. Castellano, R. Deane, A. J. Gottesdiener, et al., “ Low‐Density Lipoprotein Receptor Overexpression Enhances the Rate of Brain‐To‐Blood Aβ Clearance in a Mouse Model of β‐Amyloidosis,” Proceedings of the National Academy of Sciences 109 (2012): 15502– 15507. PMC3458349 22927427
  25. [30]Y. Chan, W. Chen, W. Wan, Y. Chen, Y. Li, and C. Zhang, “ Aβ1–42 Oligomer Induces Alteration of Tight Junction Scaffold Proteins via RAGE‐Mediated Autophagy in bEnd. 3 Cells,” Experimental Cell Research 369 (2018): 266– 274. 29856989
  26. [31]R. Chang, J. Knox, J. Chang, et al., “ Blood–Brain Barrier Penetrating Biologic TNF‐α Inhibitor for Alzheimer's Disease,” Molecular Pharmaceutics 14 (2017): 2340– 2349. 28514851
  27. [33]W. Chen, J. Xing‐Zhu, L. Yan, X.‐W. Ding, C.‐H. Miao, and J.‐W. Chen, “ Propofol Improved Hypoxia‐Impaired Integrity of Blood‐Brain Barrier via Modulating the Expression and Phosphorylation of Zonula Occludens‐1,” CNS Neuroscience & Therapeutics 25 (2019): 704– 713. 30680941 PMC6515893
  28. [34]W. Chen, Y. Chan, W. Wan, Y. Li, and C. Zhang, “ Aβ1‐42 Induces Cell Damage via RAGE‐Dependent Endoplasmic Reticulum Stress in bEnd. 3 Cells,” Experimental Cell Research 362 (2018): 83– 89. 29154819
  29. [35]Z.‐L. Chen, A. S. Revenko, A. Pradeep Singh, R. MacLeod, E. H. Norris, and S. Strickland, “ Depletion of Coagulation Factor XII Ameliorates Brain Pathology and Cognitive Impairment in Alzheimer Disease Mice,” Blood, The Journal of the American Society of Hematology 129 (2017): 2547– 2556. PMC5418637 28242605
  30. [36]X. Cheng, P. He, H. Yao, Q. Dong, R. Li, and Y. Shen, “ Occludin Deficiency With BACE1 Elevation in Cerebral Amyloid Angiopathy,” Neurology 82 (2014): 1707– 1715. 24739782 PMC4032211
  31. [37]Z. Cheng, L. Wang, Q. Meijie, et al., “ Mesenchymal Stem Cells Attenuate Blood‐Brain Barrier Leakage After Cerebral Ischemia in Mice,” Journal of Neuroinflammation 15 (2018): 1– 11. 29724240 PMC5932816
  32. [38]S. Chiquita, M. Ribeiro, J. Castelhano, et al., “ A Longitudinal Multimodal In Vivo Molecular Imaging Study of the 3xTg‐AD Mouse Model Shows Progressive Early Hippocampal and Taurine Loss,” Human Molecular Genetics 28 (2019): 2174– 2188. 30816415 PMC6586150
  33. [39]T. E. Close, G. Cepinskas, T. Omatsu, et al., “ Diabetic Ketoacidosis Elicits Systemic Inflammation Associated With Cerebrovascular Endothelial Cell Dysfunction,” Microcirculation 20 (2013): 534– 543. 23441883
  34. [40]J. A. Conquer, M. C. Tierney, J. Zecevic, W. J. Bettger, and R. H. Fisher, “ Fatty Acid Analysis of Blood Plasma of Patients With Alzheimer's Disease, Other Types of Dementia, and Cognitive Impairment,” Lipids 35 (2000): 1305– 1312. 11201991
  35. [41]M. Cortes‐Canteli, A. Kruyer, I. Fernandez‐Nueda, et al., “ Long‐Term Dabigatran Treatment Delays Alzheimer's Disease Pathogenesis in the TgCRND8 Mouse Model,” Journal of the American College of Cardiology 74 (2019): 1910– 1923. 31601371 PMC6822166
  36. [42]S. Craft, L. D. Baker, T. J. Montine, et al., “ Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment: A Pilot Clinical Trial,” Archives of Neurology 69 (2012): 29– 38. 21911655 PMC3260944
  37. [43]Y. Cui, Y. Wang, X. Song, et al., “ Brain Endothelial PTEN/AKT/NEDD4‐2/MFSD2A Axis Regulates Blood‐Brain Barrier Permeability,” Cell Reports 36 (2021): 109327. 34233198
  38. [44]A. Custodia, M. Aramburu‐Núñez, M. Rodríguez‐Arrizabalaga, et al., “ Biomarkers Assessing Endothelial Dysfunction in Alzheimer's Disease,” Cells 12 (2023): 962. 36980302 PMC10047803
  39. [45]A. Czigler, L. Toth, N. Szarka, et al., “ Prostaglandin E2, a Postulated Mediator of Neurovascular Coupling, at Low Concentrations Dilates Whereas at Higher Concentrations Constricts Human Cerebral Parenchymal Arterioles,” Prostaglandins & Other Lipid Mediators 146 (2020): 106389. 31689497
  40. [46]D. Oliveira, L. R. Cardoso, L. A. N. Mimura, et al., “ Calcitriol Prevents Neuroinflammation and Reduces Blood‐Brain Barrier Disruption and Local Macrophage/Microglia Activation,” Frontiers in Pharmacology 11 (2020): 161. 32226379 PMC7080989
  41. [47]R. Deane, S. Du Yan, R. K. Submamaryan, et al., “ RAGE Mediates Amyloid‐β Peptide Transport Across the Blood‐Brain Barrier and Accumulation in Brain,” Nature Medicine 9 (2003): 907– 913. 12808450
  42. [48]X. Deng, X. Liang, H. Yang, et al., “ Nicotinamide Mononucleotide (NMN) Protects bEnd. 3 Cells Against H2O2‐Induced Damage via NAMPT and the NF‐κB p65 Signalling Pathway,” FEBS Open Bio 11 (2021): 866– 879. PMC7931234 33340447
  43. [49]B. R. Dickie, M. Vandesquille, J. Ulloa, H. Boutin, L. M. Parkes, and G. J. M. Parker, “ Water‐Exchange MRI Detects Subtle Blood‐Brain Barrier Breakdown in Alzheimer's Disease Rats,” NeuroImage 184 (2019): 349– 358. 30219292
  44. [50]Y. Ding, Y. Zhong, A. Baldeshwiler, E. L. Abner, B. Bauer, and A. Hartz, “ Protecting P‐Glycoprotein at the Blood–Brain Barrier From Degradation in an Alzheimer's Disease Mouse Model,” Fluids and Barriers of the CNS 18 (2021): 1– 13. 33676539 PMC7937299
  45. [51]T. M. Do, B. Bedussi, S. Chasseigneaux, et al., “ Oatp1a4 and an L‐Thyroxine‐Sensitive Transporter Mediate the Mouse Blood‐Brain Barrier Transport of Amyloid‐β Peptide,” Journal of Alzheimer's Disease 36 (2013): 555– 561. 23635403
  46. [52]T. M. Do, A. Dodacki, W. Alata, et al., “ Age‐Dependent Regulation of the Blood‐Brain Barrier Influx/Efflux Equilibrium of Amyloid‐β Peptide in a Mouse Model of Alzheimer's Disease (3xTg‐AD),” Journal of Alzheimer's Disease 49 (2016): 287– 300. 26484906
  47. [53]E. Goldman, D. G. Shirin, D. Last, et al., “ High‐Fat Diet Protects the Blood–Brain Barrier in an Alzheimer's Disease Mouse Model,” Aging Cell 17 (2018): e12818. 30079520 PMC6156545
  48. [54]X. Fang, F. Fan, J. J. Border, and R. J. Roman, “ Cerebrovascular Dysfunction in Alzheimer's Disease and Transgenic Rodent Models,” Journal of Experimental Neurology 5 (2024): 42– 64. 38434588 PMC10906803
  49. [55]A. J. Farrall and J. M. Wardlaw, “ Blood–Brain Barrier: Ageing and Microvascular Disease—Systematic Review and Meta‐Analysis,” Neurobiology of Aging 30 (2009): 337– 352. 17869382
  50. [56]S. T. Ferreira, “ Brain Insulin, Insulin‐Like Growth Factor 1 and Glucagon‐Like Peptide 1 Signalling in Alzheimer's Disease,” Journal of Neuroendocrinology 33 (2021): e12959. 33739563
  51. [57]M. Fiala, Q. N. Liu, J. Sayre, et al., “ Cyclooxygenase‐2‐Positive Macrophages Infiltrate the Alzheimer's Disease Brain and Damage the Blood‐Brain Barrier,” European Journal of Clinical Investigation 32 (2002): 360– 371. 12027877
  52. [58]M. Fiala, L. Zhang, X. Gan, et al., “ Amyloid‐β Induces Chemokine Secretion and Monocyte Migration Across a Human Blood‐Brain Barrier Model,” Molecular Medicine 4 (1998): 480– 489. 9713826 PMC2230332
  53. [59]S. Freude, K. Schilbach, and M. Schubert, “ The Role of IGF‐1 Receptor and Insulin Receptor Signaling for the Pathogenesis of Alzheimer's Disease: From Model Organisms to Human Disease,” Current Alzheimer Research 6 (2009): 213– 223. 19519303
  54. [60]J. Frontiñán‐Rubio, Y. Rabanal‐Ruiz, M. Durán‐Prado, and F. J. Alcain, “ The Protective Effect of Ubiquinone Against the Amyloid Peptide in Endothelial Cells Is Isoprenoid Chain Length‐Dependent,” Antioxidants 10 (2021): 1806. 34829677 PMC8615161
  55. [61]L. Fu, G. Jiang, H. Weng, G. M. Dick, Y. Chang, and G. S. Kassab, “ Cerebrovascular miRNAs Correlate With the Clearance of Aβ Through Perivascular Route in Younger 3xTg‐AD Mice,” Brain Pathology 30 (2020): 92– 105. 31206909 PMC8018084
  56. [62]X. Fu, T. Niu, and X. Li, “ MicroRNA‐126‐3p Attenuates Intracerebral Hemorrhage‐Induced Blood‐Brain Barrier Disruption by Regulating VCAM‐1 Expression,” Frontiers in Neuroscience 13 (2019): 866. 31474826 PMC6707088
  57. [63]A. J. Furst and R. A. Lal, “ Amyloid‐β and Glucose Metabolism in Alzheimer's Disease,” Journal of Alzheimer's Disease 26 (2011): 105– 116. 21971455
  58. [64]C. C. Gali, E. Fanaee‐Danesh, M. Zandl‐Lang, et al., “ Amyloid‐Beta Impairs Insulin Signaling by Accelerating Autophagy‐Lysosomal Degradation of LRP‐1 and IR‐β in Blood‐Brain Barrier Endothelial Cells In Vitro and in 3XTg‐AD Mice,” Molecular and Cellular Neuroscience 99 (2019): 103390. 31276749 PMC6897558
  59. [65]H. Gao, M. Liang, A. Andreas Bergdahl, M. W. L. Hamren, K. Dahlman‐Wright, and B.‐O. Nilsson, “ Estrogen Attenuates Vascular Expression of Inflammation Associated Genes and Adhesion of Monocytes to Endothelial Cells,” Inflammation Research 55 (2006): 349– 353. 16977382
  60. [67]R. Giri, Y. Shen, M. Stins, et al., “ β‐Amyloid‐Induced Migration of Monocytes Across Human Brain Endothelial Cells Involves RAGE and PECAM‐1,” American Journal of Physiology‐Cell Physiology 279 (2000): C1772– C1781. 11078691
  61. [68]P. Gong, Z. Zhang, C. Zou, et al., “ Hippo/YAP Signaling Pathway Mitigates Blood‐Brain Barrier Disruption After Cerebral Ischemia/Reperfusion Injury,” Behavioural Brain Research 356 (2019): 8– 17. 30092249 PMC6193462
  62. [69]P. Gong, Z. Zhang, Q. I. Yichun Zou, et al., “ Tetramethylpyrazine Attenuates Blood‐Brain Barrier Disruption in Ischemia/Reperfusion Injury Through the JAK/STAT Signaling Pathway,” European Journal of Pharmacology 854 (2019): 289– 297. 31004602
  63. [70]S. Gustafsson, T. Gustavsson, S. Roshanbin, et al., “ Blood‐Brain Barrier Integrity in a Mouse Model of Alzheimer's Disease With or Without Acute 3D6 Immunotherapy,” Neuropharmacology 143 (2018): 1– 9. 30201212
  64. [71]M. Gynther, E. Puris, S. Peltokangas, et al., “ Alzheimer's Disease Phenotype or Inflammatory Insult Does Not Alter Function of L‐Type Amino Acid Transporter 1 in Mouse Blood‐Brain Barrier and Primary Astrocytes,” Pharmaceutical Research 36 (2019a): 1– 8. PMC6267245 30488131
  65. [73]A. M. S. Hartz, Y. Zhong, A. Wolf, H. LeVine, D. S. Miller, and B. Bauer, “ Aβ40 Reduces P‐Glycoprotein at the Blood–Brain Barrier Through the Ubiquitin–Proteasome Pathway,” Journal of Neuroscience 36 (2016): 1930– 1941. 26865616 PMC4748076
  66. [74]M. Haupt, B. Zechmeister, B. Bosche, et al., “ Lithium Enhances Post‐Stroke Blood‐Brain Barrier Integrity, Activates the MAPK/ERK1/2 Pathway and Alters Immune Cell Migration in Mice,” Neuropharmacology 181 (2020): 108357. 33065166
  67. [75]Q. He, Y. Ma, C. Fang, et al., “ Remote Ischemic Conditioning Attenuates Blood‐Brain Barrier Disruption After Recombinant Tissue Plasminogen Activator Treatment via Reducing PDGF‐CC,” Pharmacological Research 187 (2023): 106641. 36587812
  68. [76]C. Hölscher, “ Brain Insulin Resistance: Role in Neurodegenerative Disease and Potential for Targeting,” Expert Opinion on Investigational Drugs 29 (2020): 333– 348. 32175781
  69. [77]H. Hu, X.‐x. Zhang, Y.‐y. Wang, and S.‐z. Chen, “ Honokiol Inhibits Arterial Thrombosis Through Endothelial Cell Protection and Stimulation of Prostacyclin,” Acta Pharmacologica Sinica 26 (2005): 1063– 1068. 16115372
  70. [78]S. Hu, T. Liu, W. Yali, et al., “ Panax Notoginseng Saponins Suppress Lipopolysaccharide‐Induced Barrier Disruption and Monocyte Adhesion on bEnd. 3 Cells via the Opposite Modulation of Nrf2 Antioxidant and NF‐κB Inflammatory Pathways,” Phytotherapy Research 33 (2019): 3163– 3176. 31468630
  71. [79]T. Hu, R. Sun, F. Huang, et al., “ CD99 Mediates Neutrophil Transmigration Through the bEnd. 3 Monolayer via the Induction of Oxygen‐Glucose Deprivation,” Biochemical and Biophysical Research Communications 526 (2020): 799– 804. 32268960
  72. [80]X. Huang, J. Qi, S. Yixun, et al., “ Endothelial DR6 in Blood‐Brain Barrier Malfunction in Alzheimer's Disease,” Cell Death & Disease 15 (2024): 258. 38609388 PMC11014957
  73. [81]K. Hultman, S. Strickland, and E. H. Norris, “ The APOE ɛ4/ɛ4 Genotype Potentiates Vascular Fibrin(Ogen) Deposition in Amyloid‐Laden Vessels in the Brains of Alzheimer's Disease Patients,” Journal of Cerebral Blood Flow and Metabolism 33 (2013a): 1251– 1258. 23652625 PMC3734776
  74. [82]K. Hultman, S. Strickland, and E. H. Norris, “ The APOE ε4/ε4 Genotype Potentiates Vascular Fibrin (Ogen) Deposition in Amyloid‐Laden Vessels in the Brains of Alzheimer's Disease Patients,” Journal of Cerebral Blood Flow & Metabolism 33 (2013b): 1251– 1258. 23652625 PMC3734776
  75. [83]R. Hummel, S. Ulbrich, D. Appel, et al., “ Administration of All‐Trans Retinoic Acid After Experimental Traumatic Brain Injury Is Brain Protective,” British Journal of Pharmacology 177 (2020): 5208– 5223. 32964418 PMC7588818
  76. [84]J. Iannucci, W. Renehan, and P. Grammas, “ Thrombin, a Mediator of Coagulation, Inflammation, and Neurotoxicity at the Neurovascular Interface: Implications for Alzheimer's Disease,” Frontiers in Neuroscience 14 (2020): 762. 32792902 PMC7393221
  77. [85]Y. Iturria‐Medina, R. C. Sotero, P. J. Toussaint, J. M. Mateos‐Pérez, and A. C. Evans, “ Early Role of Vascular Dysregulation on Late‐Onset Alzheimer's Disease Based on Multifactorial Data‐Driven Analysis,” Nature Communications 7 (2016): 1– 14. PMC4919512 27327500
  78. [86]Y.‐B. Ji, Q. Gao, X.‐X. Tan, et al., “ Lithium Alleviates Blood‐Brain Barrier Breakdown After Cerebral Ischemia and Reperfusion by Upregulating Endothelial Wnt/β‐Catenin Signaling in Mice,” Neuropharmacology 186 (2021): 108474. 33524408
  79. [87]Y. Jia, N. Wang, Y. Zhang, D. Xue, H. Lou, and X. Liu, “ Alteration in the Function and Expression of SLC and ABC Transporters in the Neurovascular Unit in Alzheimer's Disease and the Clinical Significance,” Aging and Disease 11 (2020): 390– 404. 32257549 PMC7069460
  80. [88]J. Jung, P. Eggleton, A. Robinson, et al., “ Calnexin Is Necessary for T Cell Transmigration Into the Central Nervous System,” JCI Insight 3 (2018): e98410. 29515033 PMC5922283
  81. [89]P. K. Kamat, P. Kyles, A. Kalani, and N. Tyagi, “ Hydrogen Sulfide Ameliorates Homocysteine‐Induced Alzheimer's Disease‐Like Pathology, Blood–Brain Barrier Disruption, and Synaptic Disorder,” Molecular Neurobiology 53 (2016): 2451– 2467. 26019015 PMC4662933
  82. [90]L. A. Kasatkina, A. Heinemann, Y. A. Hudz, D. Thomas, and E. M. Sturm, “ Stearoylethanolamide Interferes With Retrograde Endocannabinoid Signalling and Supports the Blood‐Brain Barrier Integrity Under Acute Systemic Inflammation,” Biochemical Pharmacology 174 (2020): 113783. 31881191
  83. [91]X.‐j. Ke, Y.‐f. Cheng, Y. Nian, and Q. Di, “ Effects of Carbamazepine on the P‐gp and CYP3A Expression Correlated With PXR or NF‐κB Activity in the bEnd. 3 Cells,” Neuroscience Letters 690 (2019): 48– 55. 30312753
  84. [92]J. Keaney, D. M. Walsh, T. O'Malley, et al., “ Autoregulated Paracellular Clearance of Amyloid‐β Across the Blood‐Brain Barrier,” Science Advances 1 (2015): e1500472. 26491725 PMC4610013
  85. [93]D. Kellar and S. Craft, “ Brain Insulin Resistance in Alzheimer's Disease and Related Disorders: Mechanisms and Therapeutic Approaches,” Lancet Neurology 19 (2020): 758– 766. 32730766 PMC9661919
  86. [94]S. Khamchai, W. Chumboatong, J. Hata, C. Tocharus, A. Suksamrarn, and J. Tocharus, “ Morin Attenuated Cerebral Ischemia/Reperfusion Injury Through Promoting Angiogenesis Mediated by Angiopoietin‐1‐Tie‐2 Axis and Wnt/β‐Catenin Pathway,” Neurotoxicity Research 40 (2022): 1– 12. 34997920
  87. [95]N. U. Khan, T. Miao, J. Xiufeng, Q. Guo, and H. Liang, “ Brain Targeted Drug Delivery System,” in Carrier‐Mediated Transportation Through BBB (Elsevier, 2019), 129– 158.
  88. [96]M. Khoshnazar, S. Parvardeh, and M. R. Bigdeli, “ Alpha‐Pinene Exerts Neuroprotective Effects via Anti‐Inflammatory and Anti‐Apoptotic Mechanisms in a Rat Model of Focal Cerebral Ischemia‐Reperfusion,” Journal of Stroke and Cerebrovascular Diseases 29 (2020): 104977. 32689608
  89. [97]D.‐G. Kim and M. S. Bynoe, “ A2A Adenosine Receptor Regulates the Human Blood‐Brain Barrier Permeability,” Molecular Neurobiology 52 (2015): 664– 678. 25262373 PMC4439385
  90. [98]G. S. Kim, L. Yang, G. Zhang, et al., “ Critical Role of Sphingosine‐1‐Phosphate Receptor‐2 in the Disruption of Cerebrovascular Integrity in Experimental Stroke,” Nature Communications 6 (2015): 1– 15. PMC4587559 26243335
  91. [99]H. Koepsell, “ Organic Cation Transporters in Health and Disease,” Pharmacological Reviews 72 (2020): 253– 319. 31852803
  92. [100]S.‐Y. Kook, H. S. Hong, M. Moon, C. M. Ha, S. Chang, and I. Mook‐Jung, “ Aβ1–42‐RAGE Interaction Disrupts Tight Junctions of the Blood–Brain Barrier via Ca2+−Calcineurin Signaling,” Journal of Neuroscience 32 (2012): 8845– 8854. 22745485 PMC6622350
  93. [102]Y. Lamartinière, M.‐C. Boucau, L. Dehouck, et al., “ ABCA7 Downregulation Modifies Cellular Cholesterol Homeostasis and Decreases Amyloid‐β Peptide Efflux in an In Vitro Model of the Blood‐Brain Barrier,” Journal of Alzheimer's Disease 64 (2018): 1195– 1211. 30010117
  94. [103]B. A. Lamb, K. A. Bardel, L. S. Kulnane, et al., “ Amyloid Production and Deposition in Mutant Amyloid Precursor Protein and Presenilin‐1 Yeast Artificial Chromosome Transgenic Mice,” Nature Neuroscience 2 (1999): 695– 697. 10412057
  95. [104]B. K. Lee, W. J. Lee, and Y.‐S. Jung, “ Chrysin Attenuates VCAM‐1 Expression and Monocyte Adhesion in Lipopolysaccharide‐Stimulated Brain Endothelial Cells by Preventing NF‐κB Signaling,” International Journal of Molecular Sciences 18 (2017): 1424. 28671640 PMC5535915
  96. [105]D. Lee, S.‐J. Cho, H. J. Lim, et al., “ Alteration of Vascular Endothelial Cadherin in Alzheimer's Disease Patient and Mouse Model,” BioRxiv 430140 (2018): 1– 40.
  97. [106]N. Lemon, E. Canepa, M. A. Ilies, and S. Fossati, “ Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer's Disease and Stroke,” Frontiers in Aging Neuroscience 13 (2021): 772278. 34867298 PMC8635164
  98. [107]J. E. Lengfeld, S. E. Lutz, J. R. Smith, et al., “ Endothelial Wnt/β‐Catenin Signaling Reduces Immune Cell Infiltration in Multiple Sclerosis,” Proceedings of the National Academy of Sciences 114 (2017): E1168– E1177. PMC5320985 28137846
  99. [108]A.‐D. Li, L. Tong, X. Nan, et al., “ miR‐124 Regulates Cerebromicrovascular Function in APP/PS1 Transgenic Mice via C1ql3,” Brain Research Bulletin 153 (2019): 214– 222. 31499089
  100. [109]C. Li, X. Wang, F. Cheng, et al., “ Geniposide Protects Against Hypoxia/Reperfusion‐Induced Blood‐Brain Barrier Impairment by Increasing Tight Junction Protein Expression and Decreasing Inflammation, Oxidative Stress, and Apoptosis in an In Vitro System,” European Journal of Pharmacology 854 (2019): 224– 231. 30995438
  101. [110]J. Li, M. Li, Y. Ge, et al., “ β‐Amyloid Protein Induces Mitophagy‐Dependent Ferroptosis Through the CD36/PINK/PARKIN Pathway Leading to Blood–Brain Barrier Destruction in Alzheimer's Disease,” Cell & Bioscience 12 (2022a): 69. 35619150 PMC9134700
  102. [111]T. Li, L.‐N. Zheng, and X.‐H. Han, “ Fenretinide Attenuates Lipopolysaccharide (LPS)‐Induced Blood‐Brain Barrier (BBB) and Depressive‐Like Behavior in Mice by Targeting Nrf‐2 Signaling,” Biomedicine & Pharmacotherapy 125 (2020): 109680. 32106372
  103. [112]W.‐H. Li, X. Cheng, Y.‐L. Yang, et al., “ Kaempferol Attenuates Neuroinflammation and Blood Brain Barrier Dysfunction to Improve Neurological Deficits in Cerebral Ischemia/Reperfusion Rats,” Brain Research 1722 (2019): 146361. 31377105
  104. [113]H. Liang, N. Matei, D. W. McBride, et al., “ Activation of TGR5 Protects Blood Brain Barrier via the BRCA1/Sirt1 Pathway After Middle Cerebral Artery Occlusion in Rats,” Journal of Biomedical Science 27 (2020): 1– 11. 32381096 PMC7206796
  105. [114]L.‐X. Liao, M.‐B. Zhao, X. Dong, Y. Jiang, K.‐W. Zeng, and T. Peng‐Fei, “ TDB Protects Vascular Endothelial Cells Against Oxygen‐Glucose Deprivation/Reperfusion‐Induced Injury by Targeting miR‐34a to Increase Bcl‐2 Expression,” Scientific Reports 6 (2016): 37959. 27885275 PMC5122842
  106. [115]S. Liebner, R. M. Dijkhuizen, Y. Reiss, K. H. Plate, D. Agalliu, and G. Constantin, “ Functional Morphology of the Blood–Brain Barrier in Health and Disease,” Acta Neuropathologica 135 (2018): 311– 336. 29411111 PMC6781630
  107. [116]Z. Lin, S. Sur, P. Liu, et al., “ Blood–Brain Barrier Breakdown in Relationship to Alzheimer and Vascular Disease,” Annals of Neurology 90 (2021): 227– 238. 34041783 PMC8805295
  108. [117]C.‐Y. Liu, K. Bai, X.‐H. Liu, L.‐M. Zhang, and Y. Gu‐Ran, “ Hyperoside Protects the Blood‐Brain Barrier From Neurotoxicity of Amyloid Beta 1–42,” Neural Regeneration Research 13 (2018): 1974– 1980. 30233072 PMC6183045
  109. [118]C. Liu, K. Chen, L. Yunwei, Z. Fang, and Y. Guran, “ Catalpol Provides a Protective Effect on Fibrillary Aβ1–42‐Induced Barrier Disruption in an In Vitro Model of the Blood–Brain Barrier,” Phytotherapy Research 32 (2018): 1047– 1055. 29479743
  110. [119]J. Liu, Y. Bai, Y. Feng, et al., “ ABCC1 Deficiency Potentiated Noise‐Induced Hearing Loss in Mice by Impairing Cochlear Antioxidant Capacity,” Redox Biology 74 (2024): 103218. 38870779 PMC11225891
  111. [120]L.‐H. Liu, X. Jun, Y.‐L. Deng, et al., “ A Complex Association of ABCA7 Genotypes With Sporadic Alzheimer Disease in Chinese Han Population,” Alzheimer Disease & Associated Disorders 28 (2014): 141– 144. 24113560
  112. [121]Q. Liu, L. Zhu, X. Liu, et al., “ TRA2A‐Induced Upregulation of LINC00662 Regulates Blood‐Brain Barrier Permeability by Affecting ELK4 mRNA Stability in Alzheimer's Microenvironment,” RNA Biology 17 (2020): 1293– 1308. 32372707 PMC7549634
  113. [122]R. Liu, J.‐z. Li, J.‐k. Song, et al., “ Pinocembrin Improves Cognition and Protects the Neurovascular Unit in Alzheimer Related Deficits,” Neurobiology of Aging 35 (2014): 1275– 1285. 24468471
  114. [123]T. Liu, W.‐h. Liu, J.‐s. Zhao, F.‐z. Meng, and H. Wang, “ Lutein Protects Against β‐Amyloid Peptide‐Induced Oxidative Stress in Cerebrovascular Endothelial Cells Through Modulation of Nrf‐2 and NF‐κb,” Cell Biology and Toxicology 33 (2017a): 57– 67. 27878403
  115. [124]Y. Liu, M. Alahiri, B. Ulloa, B. Xie, and S. A. Sadiq, “ Adenosine A2A Receptor Agonist Ameliorates EAE and Correlates With Th1 Cytokine‐Induced Blood Brain Barrier Dysfunction via Suppression of MLCK Signaling Pathway,” Immunity, Inflammation and Disease 6 (2018): 72– 80. 29027376 PMC5818446
  116. [125]Z. Liu, S. Yan, J. Wang, et al., “ Endothelial Adenosine A2a Receptor‐Mediated Glycolysis Is Essential for Pathological Retinal Angiogenesis,” Nature Communications 8 (2017): 584. PMC5605640 28928465
  117. [126]M. A. Lopez‐Ramirez, R. Fischer, C. C. Torres‐Badillo, et al., “ Role of Caspases in Cytokine‐Induced Barrier Breakdown in Human Brain Endothelial Cells,” Journal of Immunology 189 (2012): 3130– 3139. 22896632
  118. [127]N. E. Lopez, L. Gaston, K. R. Lopez, et al., “ Early Ghrelin Treatment Attenuates Disruption of the Blood Brain Barrier and Apoptosis After Traumatic Brain Injury Through a UCP‐2 Mechanism,” Brain Research 1489 (2012): 140– 148. 23099053
  119. [128]G. Lueg, C. C. Gross, H. Lohmann, et al., “ Clinical Relevance of Specific T‐Cell Activation in the Blood and Cerebrospinal Fluid of Patients With Mild Alzheimer's Disease,” Neurobiology of Aging 36 (2015): 81– 89. 25277040
  120. [129]F. Ma, P. Sun, X. Zhang, M. H. Hamblin, and K.‐J. Yin, “ Endothelium‐Targeted Deletion of the miR‐15a/16‐1 Cluster Ameliorates Blood‐Brain Barrier Dysfunction in Ischemic Stroke,” Science Signaling 13 (2020): eaay5686. 32265338 PMC7173187
  121. [130]R. Mallick, S. Basak, and A. K. Duttaroy, “ Fatty Acids and Evolving Roles of Their Proteins in Neurological, Cardiovascular Disorders and Cancers,” Progress in Lipid Research 83 (2021): 101116. 34293403
  122. [131]J. C. L. Mamo, V. Lam, E. Brook, et al., “ Probucol Prevents Blood–Brain Barrier Dysfunction and Cognitive Decline in Mice Maintained on Pro‐Diabetic Diet,” Diabetes & Vascular Disease Research 16 (2019): 87– 97. 30156119
  123. [132]M. Manni, W. Ding, L. L. Stohl, and R. D. Granstein, “ Muramyl Dipeptide Induces Th17 Polarization Through Activation of Endothelial Cells,” Journal of Immunology 186 (2011): 3356– 3363. PMC3048901 21307291
  124. [133]C. Marchi, M. P. Adorni, P. Caffarra, et al., “ ABCA1‐and ABCG1‐Mediated Cholesterol Efflux Capacity of Cerebrospinal Fluid Is Impaired in Alzheimer's Disease,” Journal of Lipid Research 60 (2019): 1449– 1456. 31167810 PMC6672040
  125. [134]W. R. Markesbery and M. A. Lovell, “ Four‐Hydroxynonenal, a Product of Lipid Peroxidation, Is Increased in the Brain in Alzheimer's Disease,” Neurobiology of Aging 19 (1998): 33– 36. 9562500
  126. [135]M. Martin, S. Vermeiren, N. Bostaille, et al., “ Engineered Wnt Ligands Enable Blood‐Brain Barrier Repair in Neurological Disorders,” Science 375 (2022): eabm4459. 35175798
  127. [136]M. Janiurek, R. S.‐K. Mette, C. Christoffersen, K. Kucharz, and M. Lauritzen, “ Apolipoprotein M‐Bound Sphingosine‐1‐Phosphate Regulates Blood–Brain Barrier Paracellular Permeability and Transcytosis,” eLife 8 (2019): e49405. 31763978 PMC6877292
  128. [137]J. G. McLarnon, “ A Leaky Blood–Brain Barrier to Fibrinogen Contributes to Oxidative Damage in Alzheimer's Disease,” Antioxidants 11 (2021): 102. 35052606 PMC8772934
  129. [138]M. McMillin, G. Frampton, R. Tobin, et al., “ TGR 5 Signaling Reduces Neuroinflammation During Hepatic Encephalopathy,” Journal of Neurochemistry 135 (2015): 565– 576. 26179031 PMC5031412
  130. [139]S. Meister, S. E. Storck, E. Hameister, et al., “ Expression of the ALS‐Causing Variant hSOD1G93A Leads to an Impaired Integrity and Altered Regulation of Claudin‐5 Expression in an In Vitro Blood–Spinal Cord Barrier Model,” Journal of Cerebral Blood Flow & Metabolism 35 (2015): 1112– 1121. 25853911 PMC4640277
  131. [140]J. L. Milstein and H. A. Ferris, “ The Brain as an Insulin‐Sensitive Metabolic Organ,” Molecular Metabolism 52 (2021): 101234. 33845179 PMC8513144
  132. [141]A. M. Moloney, R. J. Griffin, S. Timmons, R. O'Connor, R. Ravid, and C. O'Neill, “ Defects in IGF‐1 Receptor, Insulin Receptor and IRS‐1/2 in Alzheimer's Disease Indicate Possible Resistance to IGF‐1 and Insulin Signalling,” Neurobiology of Aging 31 (2010): 224– 243. 18479783
  133. [143]A. Montagne, D. A. Nation, A. P. Sagare, et al., “ APOE4 Leads to Blood–Brain Barrier Dysfunction Predicting Cognitive Decline,” Nature 581 (2020): 71– 76. 32376954 PMC7250000
  134. [144]A. Montagne, Z. Zhao, and B. V. Zlokovic, “ Alzheimer's Disease: A Matter of Blood–Brain Barrier Dysfunction?,” Journal of Experimental Medicine 214 (2017): 3151– 3169. 29061693 PMC5679168
  135. [145]S. Moreno‐Grau, I. Hernández, S. Heilmann‐Heimbach, et al., “ Genome‐Wide Significant Risk Factors on Chromosome 19 and the APOE Locus,” Oncotarget 9 (2018): 24590– 24600. 29872490 PMC5973862
  136. [146]S. Moreno‐Grau, O. Rodríguez‐Gómez, A. Sanabria, et al., “ Exploring APOE Genotype Effects on Alzheimer's Disease Risk and Amyloid β Burden in Individuals With Subjective Cognitive Decline: The FundacioACE Healthy Brain Initiative (FACEHBI) Study Baseline Results,” Alzheimer's & Dementia 14 (2018): 634– 643. 29156223
  137. [147]M. Mulder, R. Ravid, D. F. Swaab, et al., “ Reduced Levels of Cholesterol, Phospholipids and Fatty Acids in Cerebrospinal Fluid of Alzheimer's Disease Patients Are Not Related to Apolipoprotein E4,” Alzheimer Disease and Associated Disorders 12 (1998): 198– 203. 9772023
  138. [148]P. Muszyński, A. Kulczyńska‐Przybik, R. Borawska, et al., “ The Relationship Between Markers of Inflammation and Degeneration in the Central Nervous System and the Blood‐Brain Barrier Impairment in Alzheimer's Disease,” Journal of Alzheimer's Disease 59 (2017): 903– 912. 28697565
  139. [149]W. Na, J. Y. Lee, W.‐S. Kim, T. Y. Yune, and J. Bong‐Gun, “ 17β‐Estradiol Ameliorates Tight Junction Disruption via Repression of MMP Transcription,” Molecular Endocrinology 29 (2015): 1347– 1361. 26168035 PMC5414681
  140. [150]H. Nagano, S. Ito, T. Masuda, and S. Ohtsuki, “ Effect of Insulin Receptor‐Knockdown on the Expression Levels of Blood–Brain Barrier Functional Proteins in Human Brain Microvascular Endothelial Cells,” Pharmaceutical Research (2021): 1– 14. 34811625
  141. [151]D. A. Nation, M. D. Sweeney, A. Montagne, et al., “ Blood‐Brain Barrier Breakdown Is an Early Biomarker of Human Cognitive Dysfunction,” Nature Medicine 39 (2019): 1561– 1574. PMC6367058 30643288
  142. [152]L. N. Nguyen, D. Ma, G. Shui, et al., “ Mfsd2a Is a Transporter for the Essential Omega‐3 Fatty Acid Docosahexaenoic Acid,” Nature 509 (2014): 503– 506. 24828044
  143. [153]Y.‐x. Ning, S.‐l. Ren, F.‐d. Zhao, and L.‐h. Yin, “ Overexpression of the Steroidogenic Acute Regulatory Protein Increases the Expression of ATP‐Binding Cassette Transporters in Microvascular Endothelial Cells (bEnd. 3),” Journal of Zhejiang University SCIENCE B 11 (2010): 350– 356. 20443213 PMC2865837
  144. [154]Y. Ning, S. Chen, X. Li, Y. Ma, F. Zhao, and L. Yin, “ Cholesterol, LDL, and 25‐Hydroxycholesterol Regulate Expression of the Steroidogenic Acute Regulatory Protein in Microvascular Endothelial Cell Line (bEnd. 3),” Biochemical and Biophysical Research Communications 342 (2006): 1249– 1256. 16516145
  145. [155]K. Nishitsuji, T. Hosono, T. Nakamura, B. Guojun, and M. Michikawa, “ Apolipoprotein E Regulates the Integrity of Tight Junctions in an Isoform‐Dependent Manner in an In Vitro Blood‐Brain Barrier Model,” Journal of Biological Chemistry 286 (2011): 17536– 17542. 21471207 PMC3093828
  146. [157]S. B. Oh, J. A. Kim, S. J. Park, and J.‐Y. Lee, “ Associative Interactions Among Zinc, Apolipoprotein E, and Amyloid‐β in the Amyloid Pathology,” International Journal of Molecular Sciences 21 (2020): 802. 31991844 PMC7037199
  147. [158]L. E. Oikari, R. Pandit, R. Stewart, et al., “ Altered Brain Endothelial Cell Phenotype From a Familial Alzheimer Mutation and Its Potential Implications for Amyloid Clearance and Drug Delivery,” Stem Cell Reports 14 (2020): 924– 939. 32275861 PMC7220857
  148. [159]S. Paik, R. K. Somvanshi, and U. Kumar, “ Somatostatin Maintains Permeability and Integrity of Blood‐Brain Barrier in β‐Amyloid Induced Toxicity,” Molecular Neurobiology 56 (2019): 292– 306. 29700775
  149. [160]W. M. Pardridge, “ Drug Transport Across the Blood–Brain Barrier,” Journal of Cerebral Blood Flow & Metabolism 32 (2012): 1959– 1972. 22929442 PMC3494002
  150. [161]H. J. Park, J. Y. Shin, H. N. Kim, O. Se Hee, S. K. Song, and P. H. Lee, “ Mesenchymal Stem Cells Stabilize the Blood–Brain Barrier Through Regulation of Astrocytes,” Stem Cell Research & Therapy 6 (2015): 1– 12. 26420371 PMC4588687
  151. [162]J.‐C. Park, S. H. Baik, S.‐H. Han, et al., “ Annexin A1 Restores Aβ1‐42‐Induced Blood–Brain Barrier Disruption Through the Inhibition of RhoA‐ROCK Signaling Pathway,” Aging Cell 16 (2017): 149– 161. 27633771 PMC5242298
  152. [164]R. Park, S. Y. Kook, J. C. Park, and I. Mook‐Jung, “ Aβ1–42 Reduces P‐Glycoprotein in the Blood–Brain Barrier Through RAGE–NF‐κB Signaling,” Cell Death & Disease 5 (2014): e1299. 24967961 PMC4611731
  153. [165]T. Y. Park, E. J. Baik, and S. H. Lee, “ Prostaglandin E2‐Induced Intercellular Adhesion Molecule‐1 Expression Is Mediated by cAMP/Epac Signalling Modules in bEnd. 3 Brain Endothelial Cells,” British Journal of Pharmacology 169 (2013): 604– 618. 23317035 PMC3682708
  154. [166]R. Parodi‐Rullán, J. Ghiso, E. Cabrera, A. Rostagno, and S. Fossati, “ Alzheimer's Amyloid β Heterogeneous Species Differentially Affect Brain Endothelial Cell Viability, Blood‐Brain Barrier Integrity, and Angiogenesis,” Aging Cell 19 (2020): e13258. 33155752 PMC7681048
  155. [167]C. D. Pereira, F. Martins, J. Wiltfang, and A. B. Odete, “ ABC Transporters Are Key Players in Alzheimer's Disease,” Journal of Alzheimer's Disease 61 (2018): 463– 485. 29171999
  156. [168]E. Pietronigro, E. Zenaro, and G. Constantin, “ Imaging of Leukocyte Trafficking in Alzheimer's Disease,” Frontiers in Immunology 7 (2016): 33. 26913031 PMC4753285
  157. [169]B. Polis, V. Gurevich, M. Assa, and A. O. Samson, “ Norvaline Restores the BBB Integrity in a Mouse Model of Alzheimer's Disease,” International Journal of Molecular Sciences 20 (2019): 4616. 31540372 PMC6770953
  158. [170]C. H. Poon, Y. Wang, M.‐L. Fung, C. Zhang, and L. W. Lim, “ Rodent Models of Amyloid‐Beta Feature of Alzheimer's Disease: Development and Potential Treatment Implications,” Aging and Disease 11 (2020): 1235– 1259. 33014535 PMC7505263
  159. [173]C. P. Profaci, R. N. Munji, R. S. Pulido, and R. Daneman, “ The Blood–Brain Barrier in Health and Disease: Important Unanswered Questions,” Journal of Experimental Medicine 217 (2020): e20190062. 32211826 PMC7144528
  160. [174]N. E. Propson, E. R. Roy, A. Litvinchuk, J. Köhl, and H. Zheng, “ Endothelial C3a Receptor Mediates Vascular Inflammation and Blood‐Brain Barrier Permeability During Aging,” Journal of Clinical Investigation 131 (2021): e140966. 32990682 PMC7773352
  161. [175]E. Puris, S. Auriola, P. Korhonen, et al., “ Systemic Inflammation Induced Changes in Protein Expression of ABC Transporters and Ionotropic Glutamate Receptor Subunit 1 in the Cerebral Cortex of Familial Alzheimers Disease Mouse Model,” Journal of Pharmaceutical Sciences 110 (2021): 3953– 3962. 34403652
  162. [176]W. Qin, J. Li, R. Zhu, et al., “ Melatonin Protects Blood‐Brain Barrier Integrity and Permeability by Inhibiting Matrix Metalloproteinase‐9 via the NOTCH3/NF‐κB Pathway,” Aging (Albany NY) 11 (2019): 11391– 11415. 31811815 PMC6932927
  163. [177]H. Qosa, Y. S. Batarseh, M. M. Mohyeldin, K. A. El Sayed, J. N. Keller, and A. Kaddoumi, “ Oleocanthal Enhances Amyloid‐β Clearance From the Brains of TgSwDI Mice and In Vitro Across a Human Blood‐Brain Barrier Model,” ACS Chemical Neuroscience 6 (2015): 1849– 1859. 26348065 PMC4653763
  164. [178]R. M. Ransohoff, P. Kivisäkk, and G. Kidd, “ Three or More Routes for Leukocyte Migration Into the Central Nervous System,” Nature Reviews Immunology 3 (2003): 569– 581. 12876559
  165. [180]S. Raut, R. Patel, and A. J. Al‐Ahmad, “ Presence of a Mutation in PSEN1 or PSEN2 Gene Is Associated With an Impaired Brain Endothelial Cell Phenotype In Vitro,” Fluids and Barriers of the CNS 18 (2021): 1– 16. 33413468 PMC7789219
  166. [181]C. Reitz, G. Jun, A. Naj, et al., “ Variants in the ATP‐Binding Cassette Transporter (ABCA7), Apolipoprotein E ϵ4, and the Risk of Late‐Onset Alzheimer Disease in African Americans,” JAMA 309 (2013): 1483– 1492. 23571587 PMC3667653
  167. [182]R. G. Rempe, A. M. S. Hartz, and B. Bauer, “ Matrix Metalloproteinases in the Brain and Blood–Brain Barrier: Versatile Breakers and Makers,” Journal of Cerebral Blood Flow & Metabolism 36 (2016): 1481– 1507. 27323783 PMC5012524
  168. [183]E. M. Rhea and W. A. Banks, “ Interactions of Lipids, Lipoproteins, and Apolipoproteins With the Blood‐Brain Barrier,” Pharmaceutical Research 38 (2021): 1469– 1475. 34518942 PMC8901411
  169. [184]E. M. Rhea, C. Rask‐Madsen, and W. A. Banks, “ Insulin Transport Across the Blood–Brain Barrier Can Occur Independently of the Insulin Receptor,” Journal of Physiology 596 (2018): 4753– 4765. 30044494 PMC6166047
  170. [186]S. Rom, V. Zuluaga‐Ramirez, N. L. Reichenbach, et al., “ Secoisolariciresinol Diglucoside Is a Blood‐Brain Barrier Protective and Anti‐Inflammatory Agent: Implications for Neuroinflammation,” Journal of Neuroinflammation 15 (2018): 1– 10. 29373982 PMC5787274
  171. [187]P. T. Ronaldson and T. P. Davis, “ Regulation of Blood–Brain Barrier Integrity by Microglia in Health and Disease: A Therapeutic Opportunity,” Journal of Cerebral Blood Flow & Metabolism 40 (2020): S6– S24. 32928017 PMC7687032
  172. [188]H. Rosas‐Hernandez, E. Cuevas, J. B. Raymick, B. L. Robinson, and S. Sarkar, “ Impaired Amyloid Beta Clearance and Brain Microvascular Dysfunction Are Present in the Tg‐SwDI Mouse Model of alzheimer's Disease,” Neuroscience 440 (2020): 48– 55. 32450297
  173. [189]N. J. Rupp, B. M. Wegenast‐Braun, R. Radde, M. E. Calhoun, and M. Jucker, “ Early Onset Amyloid Lesions Lead to Severe Neuritic Abnormalities and Local, but Not Global Neuron Loss in APPPS1 Transgenic Mice,” Neurobiology of Aging 32 (2011): 2324. 20970889
  174. [191]J. K. Ryu and J. G. McLarnon, “ A Leaky Blood‐Brain Barrier, Fibrinogen Infiltration and Microglial Reactivity in Inflamed Alzheimer's Disease Brain,” Journal of Cellular and Molecular Medicine 13 (2009): 2911– 2925. 18657226 PMC4498946
  175. [193]S. Salloway, T. Gur, T. Berzin, et al., “ Effect of APOE Genotype on Microvascular Basement Membrane in Alzheimer's Disease,” Journal of the Neurological Sciences 203‐204 (2002): 183– 187. 12417381
  176. [194]A. B. Salmina, Y. K. Komleva, O. L. Lopatina, and A. Birbrair, “ Pericytes in Alzheimer's Disease: Novel Clues to Cerebral Amyloid Angiopathy Pathogenesis,” Pericyte Biology in Disease 1174 (2019): 147– 166. 31147877
  177. [195]G. N. Sekhar, A. L. Fleckney, S. T. Boyanova, et al., “ Region‐Specific Blood–Brain Barrier Transporter Changes Leads to Increased Sensitivity to Amisulpride in Alzheimer's Disease,” Fluids and Barriers of the CNS 16 (2019): 1– 19. 31842924 PMC6915870
  178. [196]J. D. Sengillo, E. A. Winkler, C. T. Walker, J. S. Sullivan, M. Johnson, and B. V. Zlokovic, “ Deficiency in Mural Vascular Cells Coincides With Blood‐Brain Barrier Disruption in Alzheimer's Disease,” Brain Pathology 23 (2013): 303– 310. 23126372 PMC3628957
  179. [197]J. Shadman, N. Sadeghian, A. Moradi, S. Bohlooli, and H. Panahpour, “ Magnesium Sulfate Protects Blood–Brain Barrier Integrity and Reduces Brain Edema After Acute Ischemic Stroke in Rats,” Metabolic Brain Disease 34 (2019): 1221– 1229. 31037556
  180. [198]S. Shang, De, Y. M. Yang, H. Zhang, et al., “ Intracerebral GM‐CSF Contributes to Transendothelial Monocyte Migration in APP/PS1 Alzheimer's Disease Mice,” Journal of Cerebral Blood Flow & Metabolism 36 (2016): 1978– 1991. 27444968 PMC5094311
  181. [199]J. Shang, T. Yamashita, F. Tian, et al., “ Chronic Cerebral Hypoperfusion Alters Amyloid‐β Transport Related Proteins in the Cortical Blood Vessels of Alzheimer's Disease Model Mouse,” Brain Research 1723 (2019): 146379. 31415766
  182. [200]K. K. Singh, P. C. Shukla, A. Quan, et al., “ BRCA1 Is a Novel Target to Improve Endothelial Dysfunction and Retard Atherosclerosis,” Journal of Thoracic and Cardiovascular Surgery 146, no. 949‐60 (2013): e4. 23415688
  183. [201]E. R. Skinner, C. Watt, J. A. O. Besson, and P. V. Best, “ Differences in the Fatty Acid Composition of the Grey and White Matter of Different Regions of the Brains of Patients With Alzheimer's Disease and Control Subjects,” Brain 116 (1993): 717– 725. 8513399
  184. [202]L. C. D. Smyth, H. C. Murray, M. Hill, et al., “ Neutrophil‐Vascular Interactions Drive Myeloperoxidase Accumulation in the Brain in Alzheimer's Disease,” Acta Neuropathologica Communications 10 (2022): 38. 35331340 PMC8944147
  185. [203]M. Sole, M. Esteban‐Lopez, B. Taltavull, et al., “ Blood‐Brain Barrier Dysfunction Underlying Alzheimer's Disease Is Induced by an SSAO/VAP‐1‐Dependent Cerebrovascular Activation With Enhanced Aβ Deposition,” Biochimica et Biophysica Acta (BBA)–Molecular Basis of Disease 1865 (2019): 2189– 2202. 31047972
  186. [204]R. Solito, F. Corti, C.‐H. Chen, et al., “ Mitochondrial Aldehyde Dehydrogenase‐2 Activation Prevents β‐Amyloid‐Induced Endothelial Cell Dysfunction and Restores Angiogenesis,” Journal of Cell Science 126 (2013): 1952– 1961. 23447675 PMC3666252
  187. [205]D. Song, X. Jiang, Y. Liu, Y. Sun, S. Cao, and Z. Zhang, “ Asiaticoside Attenuates Cell Growth Inhibition and Apoptosis Induced by Aβ1‐42 via Inhibiting the TLR4/NF‐κB Signaling Pathway in Human Brain Microvascular Endothelial Cells,” Frontiers in Pharmacology 9 (2018): 28. 29441018 PMC5797575
  188. [206]J. Song, S.‐M. Choi, D. J. Whitcomb, and B. C. Kim, “ Adiponectin Controls the Apoptosis and the Expression of Tight Junction Proteins in Brain Endothelial Cells Through AdipoR1 Under Beta Amyloid Toxicity,” Cell Death & Disease 8 (2017): e3102. 29022894 PMC5682657
  189. [207]J. Song, S. M. Kang, W. T. Lee, K. A. Park, K. M. Lee, and J. E. Lee, “ Glutathione Protects Brain Endothelial Cells From Hydrogen Peroxide‐Induced Oxidative Stress by Increasing nrf2 Expression,” Experimental Neurobiology 23 (2014): 93– 103. 24737944 PMC3984961
  190. [208]S. F. Spampinato, S. Merlo, Y. Sano, T. Kanda, and M. A. Sortino, “ Protective Effect of the Sphingosine‐1 Phosphate Receptor Agonist Siponimod on Disrupted Blood Brain Barrier Function,” Biochemical Pharmacology 186 (2021): 114465. 33577891
  191. [209]S. M. Stamatovic, R. F. Keep, M. M. Wang, I. Jankovic, and A. V. Andjelkovic, “ Caveolae‐Mediated Internalization of Occludin and Claudin‐5 During CCL2‐Induced Tight Junction Remodeling in Brain Endothelial Cells,” Journal of Biological Chemistry 284 (2009): 19053– 19066. 19423710 PMC2707189
  192. [210]E. Steen, B. M. Terry, E. J. Rivera, et al., “ Impaired Insulin and Insulin‐Like Growth Factor Expression and Signaling Mechanisms in Alzheimer's Disease–Is This Type 3 Diabetes?,” Journal of Alzheimer's Disease 7 (2005): 63– 80. 15750215
  193. [211]S. E. Storck, A. M. S. Hartz, J. Bernard, et al., “ The Concerted Amyloid‐Beta Clearance of LRP1 and ABCB1/P‐Gp Across the Blood‐Brain Barrier Is Linked by PICALM,” Brain, Behavior, and Immunity 73 (2018): 21– 33. 30041013 PMC7748946
  194. [212]F. Storelli, S. Billington, A. R. Kumar, and J. D. Unadkat, “ Abundance of P‐Glycoprotein and Other Drug Transporters at the Human Blood‐Brain Barrier in Alzheimer's Disease: A Quantitative Targeted Proteomic Study,” Clinical Pharmacology & Therapeutics 109 (2021): 667– 675. 32885413 PMC7902298
  195. [213]E. Suberbielle, B. Djukic, M. Evans, et al., “ DNA Repair Factor BRCA1 Depletion Occurs in Alzheimer Brains and Impairs Cognitive Function in Mice,” Nature Communications 6 (2015): 8897. PMC4674776 26615780
  196. [214]M. D. Sweeney, A. P. Sagare, and B. V. Zlokovic, “ Blood–Brain Barrier Breakdown in Alzheimer Disease and Other Neurodegenerative Disorders,” Nature Reviews Neurology 14 (2018): 133– 150. 29377008 PMC5829048
  197. [215]L. Szablewski, “ Glucose Transporters in Brain: In Health and in Alzheimer's Disease,” Journal of Alzheimer's Disease 55 (2017): 1307– 1320. 27858715
  198. [217]J. Tang, Y. Kang, L. Huang, W. Lei, and Y. Peng, “ TIMP1 Preserves the Blood–Brain Barrier Through Interacting With CD63/Integrin β1 Complex and Regulating Downstream FAK/RhoA Signaling,” Acta Pharmaceutica Sinica B 10 (2020): 987– 1003. 32642407 PMC7332810
  199. [219]K. P. Townsend, D. Obregon, A. Quadros, et al., “ Proinflammatory and Vasoactive Effects of Aβ in the Cerebrovasculature,” Annals of the New York Academy of Sciences 977 (2002): 65– 76. 12480734
  200. [220]V. Skike, E. Candice, J. B. Jahrling, et al., “ Inhibition of mTOR Protects the Blood‐Brain Barrier in Models of Alzheimer's Disease and Vascular Cognitive Impairment,” American Journal of Physiology‐Heart, and Circulatory Physiology 314 (2018): H693– H703. 29351469 PMC5966773

200 of 262 shown

Cited by

Sorted by citations

Authors
Yue, Q., Leng, X., Xie, N., Zhang, Z., Yang, D., & Hoi, M. P. M.
Affiliations
  • Jinan University (CN)
  • University of Macau (MO)
Corresponding author
  • Yang, Deguang
  • Hoi, Maggie Pui Man
ORCID
Venue
CNS Neuroscience & Therapeutics
Publisher
Wiley
Published
2024-11
Volume
30
Issue
11
Pages
e70079-e70079
ISSN
  • 1755-5930 (ISSN-L)
  • 1755-5949
DOI
10.1111/cns.70079
PMC
PMC11567945
OpenAlex
W4404431942
Cited by
48
References
15
Citations by year
2026: 33 · 2025: 15
FWCI
2.45
Type
journal article
Language
en
Open access
Licence
Locations
  • CNS Neuroscience & Therapeutics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Fundo para o Desenvolvimento das Ciências e da Tecnologia (0035/2020/AGJ, 0023/2020/AFJ)
  • National Natural Science Foundation of China (82061160374, 82404892)
  • Fundamental Research Funds for the Central Universities (21623114)
  • Natural Science Foundation of Guangdong Province (2024A1515012818)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
Alzheimer's disease, blood-brain barrier disruption, brain endothelial cells, paracellular permeability, ABC transporters, efflux pumps, neuroinflammation, oxidative stress, amyloid-beta deposition, cognitive decline, neuroprotection, pericytes, astrocytes
MeSH terms
Alzheimer Disease, Animals, Blood-Brain Barrier, Humans, Endothelial Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review