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Apolipoprotein E controls cerebrovascular integrity via cyclophilin A
Open accessAbstract
Human apolipoprotein E has three isoforms: APOE2, APOE3 and APOE4. APOE4 is a major genetic risk factor for Alzheimer's disease and is associated with Down's syndrome dementia and poor neurological outcome after traumatic brain injury and haemorrhage. Neurovascular dysfunction is present in normal APOE4 carriers and individuals with APOE4-associated disorders. In mice, lack of Apoe leads to blood-brain barrier (BBB) breakdown, whereas APOE4 increases BBB susceptibility to injury. How APOE genotype affects brain microcirculation remains elusive. Using different APOE transgenic mice, including mice with ablation and/or inhibition of cyclophilin A (CypA), here we show that expression of APOE4 and lack of murine Apoe, but not APOE2 and APOE3, leads to BBB breakdown by activating a proinflammatory CypA-nuclear factor-κB-matrix-metalloproteinase-9 pathway in pericytes. This, in turn, leads to neuronal uptake of multiple blood-derived neurotoxic proteins, and microvascular and cerebral blood flow reductions. We show that the vascular defects in Apoe-deficient and APOE4-expressing mice precede neuronal dysfunction and can initiate neurodegenerative changes. Astrocyte-secreted APOE3, but not APOE4, suppressed the CypA-nuclear factor-κB-matrix-metalloproteinase-9 pathway in pericytes through a lipoprotein receptor. Our data suggest that CypA is a key target for treating APOE4-mediated neurovascular injury and the resulting neuronal dysfunction and degeneration.
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“In a transgenic mouse carrying human APOE4 (a major genetic risk factor for AD), APOE4 secreted from astrocytes was found to bind with LRP1 on pericytes and induce uncontrollably proinflammatory CypA expression in pericytes, inducing the activation of NF-kB and matrix metalloproteinase 9 (MMP9),183,501”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [183]
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In the citing paper
“In addition, reduced expression of tight junction proteins was found in AD mouse model with increased MMP9 activities.183”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [183]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“For example, astrocytes secrete apolipoprotein E (APOE) to signal pericytes via low-density lipoprotein receptor-related protein-1 (LRP1), which suppress the activation of cyclophilin A (CypA)-matrix metalloproteinase 9 (MMP-9) BBB-degrading pathway, while in the absence of murine APOE mouse pericytes produce active MMP-9 causing BBB breakdown (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Studies in transgenic mice expressing human APOE isoforms have shown that astrocyte-secreted APOE2 and APOE3 bind to LRP1 on pericytes in vivo, which inhibits the proinflammatory CypA-MMP-9 pathway preventing degradation of BBB TJ and basement membrane proteins (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“APOE exerts toxic effects on the cerebrovascular system (694) and neurons (383, 384) and influences A 𝛃 clearance (60, 64, 98, 135, 256, 266, 278, 294, 315, 693), amyloid deposition (39, 256, 258, 266, 278, 314, 518, 612), and tau-related neurodegeneration (533) in an allele-dependent manner APOE4 > APOE3 > APOE2 .”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
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“Apoe -/ -mice also develop secondary neurodegenerative changes after BBB breakdown in the absence of A 𝛃 pathology (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Neuroinflammation is another key hallmark in AD brain.[ 23 ]”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [23]
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“Together this comprises a disease spectrum likely linked by deposition of amyloid-β in arterioles in the central nervous system combined with degradation of the blood-brain barrier, which collectively leaves a frail intracerebral vasculature prone to atherosclerotic cerebrovascular disease [17,31,32].”
From APOE and vascular disease: Sequencing and genotyping in general population cohorts (2023) · cites this paper as [17]
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In the citing paper
“apoE is a central apolipoprotein in cerebral cholesterol metabolism and is involved in brain amyloid metabolism, blood brain barrier integrity, and transport of various lipid species to neuronal cells [15][16][17][18][19].”
From APOE and vascular disease: Sequencing and genotyping in general population cohorts (2023) · cites this paper as [17]
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In the citing paper
“The similar findings presently observed for rare APOE variants with low apoE may reflect that the intracerebral vasculature, brain tissue and blood-brain barrier are dependent on normal levels of apoE for sufficient local lipid transport and βamyloid clearance [17,18,31,43].”
From APOE and vascular disease: Sequencing and genotyping in general population cohorts (2023) · cites this paper as [17]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Whereas brain apoE plays a major role in brain amyloid metabolism, in blood‐brain barrier integrity, and in supplying cholesterol and phospholipids to neuronal cells, 12 , 13 , 14 , 16 , 30 , 31”
From APOE and dementia – resequencing and genotyping in 105,597 individuals (2020) · cites this paper as [12]
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“Pericyte inflammation leads to neuronal uptake of neurotoxic proteins from the blood, and microvascular and cerebral blood flow reductions, which altogether subsequently lead to impaired clearance of amyloid-b [86,87].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [87]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“peripheral APOE seems to influence the brain partly by impacting the BBB.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [183]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“When compared with wild-type mice, both Apoe knockout mice and mice expressing APOE4 have a leaky BBB, a phenomenon also reported in cognitively unimpaired and mildly impaired individuals who carry an APOEε4 allele183–185.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [183]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“APOE4 alters the integrity of the blood brain barrier (BBB) influencing metabolite exchange between the periphery and the central nervous system (CNS) including reduced brain glucose and lipid transport [17][18][19] .”
From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [17]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“This hypothesis was the initial driver that defined a plethora of surprising functions of LDL receptor-related proteins (LRPs) in the central and peripheral nervous system (Bal et al., 2013; Beffert et al., 2005; Bell et al., 2012; Choi et al., 2013; Kim et al., 2008; Lane-Donovan and Herz, 2017; Liu et al., 2013; Liu et al., 2007; Liu et al., 2011; May et al., 2004; Nakajima et al., 2013; Pohl”
From Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease (2018) · cites this paper as Bell et al., 2012
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In the citing paper
“Transgenic expression of human APOE4 in the mice led to uncontrolled expression of proinflammatory cyclophilin A (CypA) in pericytes, inducing the activation of NF-kB and matrix metalloproteinase 9 (MMP9), which in turn results in BBB breakdown.183”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [183]
The cited source says what the claim attributes to it.
In the citing paper
“Transgenic mice lacking Apoe also develop an early BBB breakdown (60, 99, 147, 187, 226, 233, 406, 426, 437, 554), indicating that APOE is essential for maintaining BBB integrity.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
The cited source says what the claim attributes to it.
In the citing paper
“Additionally, LRP1 on pericytes regulates cerebrovascular integrity in an APOE-dependent fashion (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
The cited source says what the claim attributes to it.
In the citing paper
“On the other hand, APOE4 has a low affinity for LRP1, which activates CypA-MMP-9 pathway causing BBB breakdown (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
The cited source says what the claim attributes to it.
In the citing paper
“Transgenic mice expressing human APOE4 gene, but not APOE3 and APOE 2, develop an early BBB breakdown (60, 437), cerebral microhemorrhages (85), and loss of endothelial GLUT1 expression (9) that is followed by secondary neurodegenerative changes (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
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In the citing paper
“Inhibition of CypA-MMP-9 BBB degrading pathway by cyclosporine, a CypA inhibitor, restored BBB integrity and reversed secondary neurodegenerative changes in transgenic humanized APOE4 mice (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
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In the citing paper
“These vascular changes precede neuronal dysfunction and neurodegeneration, but can be reversed by sealing the BBB (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
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In the citing paper
“However, recent evidence indicates that apoE4 expression compromises the blood-brain barrier (as does apoE deficiency).40”
From Effects of the Absence of Apolipoprotein E on Lipoproteins, Neurocognitive Function, and Retinal Function (2014) · cites this paper as [40]
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In the citing paper
“Both the level of apoE and apoE isoform plays a role: lack of murine Apoe protein as well as targeted replacement of murine Apoe with human apoE4, leads to blood-brain barrier breakdown by activating a proinflammatory cyclophilin A-nuclear factor kB-matrix metalloproteinase-9 pathway in pericytes [87].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [87]
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In the citing paper
“vascular defects have been detected in human apoE4-targeted replacement (apoE4-TR) mice, but not apoE3-TR mice, at 2 weeks of age”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Bell et al 2012
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In the citing paper
“Moreover, as inflammatory factors including IL‐1, IL‐6, GM‐CSF, IL‐12 and IL‐23, and TNF‐α were all upregulated under AD condition.[ 23 ]”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [23]
Experimental — accuracy not yet measuredIn the citing paper
“inflammatory cell infiltrates were noted pathologically over 110 years ago in the penetrating arterioles and perivascular tissue in SVD,60 and consistently ever since (Figure 5, Supplementary Figure 3);19 plasma inflammatory markers are elevated in lacunar stroke56,127 and also associated genetically with WMH progression and lacunar infarcts.128”
From Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging (2013) · cites this paper as [127]
In the citing paper
“Activation of this pathway causes MMP-9-mediated degradation of endothelial tight junctions and basement membrane proteins, as shown in human ApoE4 targeted replacement mice (Bell et al., 2012).”
From The Pathobiology of Vascular Dementia (2013) · cites this paper as Bell et al., 2012
In the citing paper
“ApoE4, a major genetic risk factor for AD, leads to BBB disruption through a proinflammatory pathway involving cyclophilin A in pericytes (Bell et al., 2012).”
From The Pathobiology of Vascular Dementia (2013) · cites this paper as Bell et al., 2012
In the citing paper
“Of note, APOE4 also triggered inflammatory cascades, leading to neurovascular dysfunction, degeneration of the BBB, consequent penetration of toxic proteins from blood into the brain and reduced length of small blood vessels [466].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [466]
In the citing paper
“ApoE4 may also mediate neuropathological effects by directly modulating BBB integrity”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Bell et al., 2012
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“…et al., 2010, Halliday et al., 2016, Hultman et al., 2013, Sengillo et al., 2013), and expression of the E4 isoform of apolipoprotein E, a strong genetic risk factor of developing AD (Hauser and Ryan, 2013, Michaelson, 2014), has been shown to lead to BBB breakdown in mice (Bell et al., 2012).”
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“the neurodegenerative disease phenotype [122].”
Age Drives Distortion of Brain Metabolic, Vascular and Cognitive Functions, and the Gut Microbiome
Hoffman, J. D., Parikh, I. J., Green, S. J., Chlipala, G. E., Mohney, R. P., Keaton, M., Bauer, B., Hartz, A. M. S., & Lin, A. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00298 · Cited by 124
“The reduction of BBB transporters may lead to impaired clearance of Aβ (Zlokovic, 2011; Bell et al., 2012), enhancing the risk of dementia like symptoms (Erickson and Banks, 2013).”
BackgroundEffects of a Disrupted Blood-Brain Barrier on Cholesterol Homeostasis in the Brain
Saeed, A. A., Genové, G., Li, T. X., Lütjohann, D., Olin, M., Mast, N., Pikuleva, I. A., Crick, P. J., Wang, Y., Griffiths, W. J., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.556159 · Cited by 124
“It was also recently reported that lack of the cholesterol transporter ApoE or the presence of the isoform ApoE4 leads to BBB dysfunction (3).”
BackgroundSelf-citationBlair, L. J., Baker, J. D., Sabbagh, J. J., & Dickey, C. A. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13033 · Cited by 120
Halliday, M. R., Pomara, N., Sagare, A. P., Mack, W. J., Frangione, B., & Zlokovic, B. V. (2013) · JAMA Neurology · doi:10.1001/jamaneurol.2013.3841 · Cited by 119
Self-citationAlzheimer's Disease Mechanisms and Emerging Roads to Novel Therapeutics
Sala Frigerio, C., & De Strooper, B. (2016) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-070815-014015 · Cited by 116
Interaction of Age and APOE Genotype on Cerebral Blood Flow at Rest
Wierenga, C. E., Clark, L. R., Dev, S. I., Shin, D. D., Jurick, S. M., Rissman, R. A., Liu, T. T., & Bondi, M. W. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-121897 · Cited by 126
“For example, a recent study demonstrated that possession of the APOE ε4 allele in mice triggered an inflammatory response that damaged the blood-brain barrier and led to cerebrovascular damage including small vessel damage [82].”
Lane-Donovan, C., Wong, W. M., Durakoglugil, M. S., Wasser, C. R., Jiang, S., Xian, X., & Herz, J. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.1054-16.2016 · Cited by 115
Liraz, O., Boehm-Cagan, A., & Michaelson, D. M. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-16 · Cited by 118
“Recent in vivo and in vitro studies revealed that apoE4 impairs the blood brain barrier (BBB) [94,95].”
BackgroundResultInfluentialImpact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer’s disease
Shinohara, M., Murray, M. E., Frank, R. D., Shinohara, M., DeTure, M., Yamazaki, Y., Tachibana, M., Atagi, Y., Davis, M. D., Liu, C.-C., et al. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1580-y · Cited by 123
“Furthermore, apoE4-TR mice exhibit dysregulated blood–brain barrier integrity and reduced brain microcirculation compared to apoE2-TR and apoE3-TR mice [6].”
IGF-1 Deficiency Impairs Cerebral Myogenic Autoregulation in Hypertensive Mice
Tóth, P., Tucsek, Z., Tarantini, S., Sosnowska, D., Gautam, T., Mitschelen, M. C., Koller, Á., Sonntag, W. E., Csiszár, A., & Ungvari, Z. I. (2014) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2014.156 · Cited by 117
The contribution of glial cells to Huntington's disease pathogenesis
Wilton, D. K., & Stevens, B. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104963 · Cited by 112
Hadass, O., Tomlinson, B. N., Gooyit, M., Chen, S., Purdy, J. J., Walker, J. M., Zhang, C., Giritharan, A. B., Purnell, W., Robinson, C. R., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076904 · Cited by 120
The Blood–Brain Barrier, Oxidative Stress, and Insulin Resistance
Banks, W. A., & Rhea, E. M. (2021) · Antioxidants · doi:10.3390/antiox10111695 · Cited by 120
“The apoE4 isoform increases the activation of the cyclophilin A-MMP-9 pathway, leading to BBB disruption [53,54], which could be mediated by oxidative stress [55].”
Chen, Y., He, Y., Han, J., Wei, W., & Chen, F. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1258640 · Cited by 116
“ApoE4 transgenic model mice showed an increase in BBB vulnerability (Nishitsuji et al., 2011; Bell et al., 2012), while the BBB integrity of mice carrying ApoE2 and ApoE3 was not affected (Bell et al., 2012).”
BackgroundGlial-endothelial crosstalk regulates blood–brain barrier function
Cheslow, L., & Alvarez, J. I. (2015) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2015.09.010 · Cited by 118
RETRACTED: ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery
Xu, H., Cao, Y., Yang, X., Cai, P., Kang, L., Zhu, X., Luo, H., Lu, L., Wei, L., Bai, X., et al. (2017) · Blood · doi:10.1182/blood-2016-10-747089 · Cited by 112
RetractedAn Integrated View on Vascular Dysfunction in Alzheimer’s Disease
Klohs, J. (2019) · Neurodegenerative Diseases · doi:10.1159/000505625 · Cited by 111
Rodríguez-Giraldo, M., González-Reyes, R. E., Ramírez-Guerrero, S., Bonilla-Trilleras, C. E., Guardo-Maya, S., & Nava-Mesa, M. O. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113630 · Cited by 122
Dan, M., Xu, L., Shao, A., Cheng, X., Zhang, C., Yokel, R. A., Takemura, T., Hanagata, N., Niwa, M., & Watanabe, D. (2015) · International Journal of Nanomedicine · doi:10.2147/ijn.s85265 · Cited by 112
ApoE and Neurodegenerative Diseases in Aging
Yin, Y., & Wang, Z. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-1117-8_5 · Cited by 111
Xiao, M., Xiao, Z. J., Yang, B., Lan, Z., & Fang, F. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00764 · Cited by 119
Reduction in DHA transport to the brain of mice expressing human APOE 4 compared to APOE 2
Vandal, M., Alata, W., Tremblay, C., Rioux‐Perreault, C., Salem, N., Calon, F., & Plourde, M. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12640 · Cited by 124
Endothelial Cells and Human Cerebral Small Vessel Disease
Hainsworth, A. H., Oommen, A. T., & Bridges, L. (2014) · Brain Pathology · doi:10.1111/bpa.12224 · Cited by 109
Shimizu, F., Sano, Y., Tominaga, O., Maeda, T., Abe, M., & Kanda, T. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.01.012 · Cited by 109
“, using in vivo ApoE-deficient and ApoE4-expressing mice, also showed that the NF-kb activation induced by cyclophilin A (CyA) leads to transcriptional upregulation of MMP-9 by pericytes (Bell et al., 2012).”
Role of phosphatidylcholine‐DHA in preventing APOE4‐associated Alzheimer's disease
Patrick, R. P. (2018) · The FASEB Journal · doi:10.1096/fj.201801412r · Cited by 118
Rodent Models of Vascular Cognitive Impairment
Yang, Y. R., Kimura‐Ohba, S., Thompson, J., & Rosenberg, G. A. (2016) · Translational Stroke Research · doi:10.1007/s12975-016-0486-2 · Cited by 109
“APOE4 transgenic mice by inhibiting cyclophilin A-MMP-9 pathway in pericytes leading to reversal of neuronal dysfunction and secondary neurodegenerative changes [80].”
‘Sealing off the CNS’: cellular and molecular regulation of blood–brain barriergenesis
Siegenthaler, J. A., Sohet, F., & Daneman, R. (2013) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2013.06.006 · Cited by 115
“Pericytes have recently been implicated in the postnatal and adult BBB defects observed in apolipoprotein E (ApoE) knockout mice [20].”
BackgroundAnalysis of Salivary Microbiome in Patients with Alzheimer’s Disease
Liu, X., Jiao, B., Liao, X., Guo, L., Yuan, Z., Wang, X., Xiao, X., Zhang, X., Tang, B., & Shen, L. H. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190587 · Cited by 110
“Recently, a research demonstrated that APOE (cid:2) 4 could activate matrix metalloproteinase 9 (MMP9) via cyclophilin A (CypA) [41].”
Vascular Dementia and Underlying Sex Differences
Akhter, F., Persaud, A., Zaokari, Y., Zhao, Z., & Zhu, D. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.720715 · Cited by 119
Chen, Y., Qian, X., Zhang, Y., Su, W., Huang, Y., Wang, X., Chen, X., Zhao, E., Han, L., & Ma, Y. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.840386 · Cited by 119
“…APOE4 causes the disinhibition of the cyclophilin A signaling mechanism in the pericytes of the brain blood vessels, leading to a degeneration of these vessels, leakage of the blood-brain barrier, and tau-induced neurodegeneration and atrophy (Bell et al., 2012; Serrano-Pozo et al., 2021).”
Stone, J., Johnstone, D. M., Mitrofanis, J., & O’Rourke, M. F. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-141884 · Cited by 113
Seo, D.-O., & Holtzman, D. M. (2019) · The Journals of Gerontology Series A · doi:10.1093/gerona/glz262 · Cited by 109
“Notably, this signaling is suppressed in ApoE3, but not ApoE4 expressing mice (76).”
BackgroundSelf-citationDuong, M. T., Nasrallah, I. M., Wolk, D. A., Chang, C. C. Y., & Chang, T. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.647990 · Cited by 110
Interplay between Brain Pericytes and Endothelial Cells in Dementia
Procter, T. V., Williams, A., & Montagne, A. (2021) · The American Journal of Pathology · doi:10.1016/j.ajpath.2021.07.003 · Cited by 106
“The increase in MMP9 was mediated by CypA in pericytes.(118) Blockage and/or pharmacologic treatment of MMP9 and CypA reversed BBB leakage, demonstrating that dysregulation of these pathways alone can be responsible for BBB disruption.”
BackgroundInfluentialNAD+ rescues aging-induced blood-brain barrier damage via the CX43-PARP1 axis
Zhan, R., Meng, X., Tian, D., Xu, J., Cui, H., Yang, J., Xu, Y., Shi, M., Xue, J., Yu, W., et al. (2023) · Neuron · doi:10.1016/j.neuron.2023.08.010 · Cited by 109
APOE-related biomarker profiles in non-pathological aging and early phases of Alzheimer's disease
Reinvang, I., Espeseth, T., & Westlye, L. T. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.05.006 · Cited by 109
Blood–brain barrier and its function during inflammation and autoimmunity
Sonar, S. A., & Lal, G. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.1ru1117-428r · Cited by 114
Jeong, W., Lee, H. G., Cho, S., & Seo, J. (2019) · PubMed Central · doi:10.14348/molcells.2019.0200 · Cited by 104
“Multiple studies suggest that ApoE4 leads to BBB leakage through the degeneration of pericytes and the disruption of the integrity of tight junctions (Casey et al., 2015; Nishitsuji et al., 2011), which leads to the accumulation of serum proteins in the brain (Bell et al., 2012).”
BackgroundCerebral Small Vessel Disease and Alzheimer's Disease: A Review
Kim, H. W., Hong, J., & Jeon, J. C. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.00927 · Cited by 111
“In developing cerebral SVD, the expression of APOE ε4, but not of APOE ε2 or of APOE ε3, leads to BBB breakdown through the activation of an NF-kB/matrix metalloproteinase 9 pathway in pericytes (47).”
BackgroundThe Glymphatic System: A Novel Therapeutic Target for Stroke Treatment
Lv, T., Zhao, B., Hu, Q., & Zhang, X. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.689098 · Cited by 107
Effect of Anserine/Carnosine Supplementation on Verbal Episodic Memory in Elderly People
Hisatsune, T., Kaneko, J., Kurashige, H., Cao, Y., Satsu, H., Totsuka, M., Katakura, Y., Imabayashi, E., & Matsuda, H. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-150767 · Cited by 106
“Authors’ disclosures available online (http://j-alz. com/manuscript-disclosures/15-0767r1).”
Age‐Associated White Matter Lesions: The MRC C ognitive F unction and A geing S tudy
Wharton, S. B., Simpson, J. E., Brayne, C., & Ince, P. G. (2014) · Brain Pathology · doi:10.1111/bpa.12219 · Cited by 105
“APOE genotype, for example, may affect BBB integrity and neurovascular unit function (4, 31).”
BackgroundInteractions between inflammation, sex steroids, and Alzheimer’s disease risk factors
Uchoa, M. F., Moser, V. A., & Pike, C. J. (2016) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2016.09.001 · Cited by 105
“Interestingly, apoE4 has less affinity for LPR1 than do apoE2 and apoE3 (Bell et al., 2012).”
Border-associated macrophages in the central nervous system
Sun, R., & Jiang, H. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03059-x · Cited by 120
Distinct Patterns of Cerebral Extravasation by Evans Blue and Sodium Fluorescein in Rats
Yen, L. F., Wei, V. C., Kuo, E. Y., & Lai, T. W. (2013) · PLoS ONE · doi:10.1371/journal.pone.0068595 · Cited by 106
Biphasic Mechanisms of Neurovascular Unit Injury and Protection in CNS Diseases
Maki, T., Hayakawa, K., Pham, L. D., Xing, C., Lo, E. H., & Arai, K. (2013) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527311312030004 · Cited by 103
“Subsequently, the pericytic MMP-9 causes neurovascular defects along with neuronal and synaptic degeneration [127].”
BackgroundZhao, Y., Li, Y., Zhao, J., Song, J., & Zhao, Y. (2016) · Reviews in the Neurosciences · doi:10.1515/revneuro-2015-0069 · Cited by 109
“A LRP-1-related mechanism that leads to BBB breakdown has been newly proposed, that is, through activating a LRP-1-dependent CypA-NF-κB-MMP-9 pathway (Bell et al., 2012; Halliday et al., 2016).”
BackgroundNew Insight Into Neutrophils: A Potential Therapeutic Target for Cerebral Ischemia
Chen, R., Zhang, X., Gu, L., Zhu, H., Zhong, Y., Ye, Y., Xiong, X., & Jian, Z. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.692061 · Cited by 105
Plasma Based Markers of [11C] PiB-PET Brain Amyloid Burden
Kiddle, S. J., Thambisetty, M., Simmons, A., Riddoch-Contreras, J., Hye, A., Westman, E., Pike, I., Ward, M., Johnston, C., Lupton, M. K., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044260 · Cited by 100
“More recently, APOE and matrix metalloproteinase-9 have been shown to be involved together in the breakdown of the blood brain barrier, which can initiate neurodegeneration [37].”
Endothelial Dysfunction in Neurodegenerative Diseases
Fang, Y., Hsieh, Y., Hu, C., & Tu, Y. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032909 · Cited by 102
Phosphodiesterase III inhibitor promotes drainage of cerebrovascular β‐amyloid
Maki, T., Okamoto, Y., Carare, R. O., Hase, Y., Hattori, Y., Hawkes, C. A., Saitô, S., Yamamoto, Y., Terasaki, Y., Ishibashi‐Ueda, H., et al. (2014) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.79 · Cited by 101
Lee, J. Y., Choi, H. Y., Ahn, H., Ju, B. G., & Yune, T. Y. (2014) · American Journal Of Pathology · doi:10.1016/j.ajpath.2014.07.016 · Cited by 103
“Furthermore, the pericyteeendothelial cell interaction also is involved in endothelial MMP-9 production in brain capillary endothelial cell cultures,(70) and a recent report shows that pericytes can also disrupt the endothelial CNS barrier by activating cyclophilin A/NF-kB/MMP-9 pathway through a lipoprotein receptor.…”
BackgroundHigh-Density Lipoproteins and Cerebrovascular Integrity in Alzheimer’s Disease
Stukas, S. K., Robert, J., & Wellington, C. L. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.01.003 · Cited by 101
“Importantly, these vascular defects precede neuronal dysfunction (Bell et al., 2012).”
BackgroundBridges, L., Andoh, J., Lawrence, A. J., Khoong, C. H. L., Poon, W. W., Esiri, M. M., Markus, H. S., & Hainsworth, A. H. (2014) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0000000000000124 · Cited by 98
“Pericyte-dependent signaling seems to be a key factor linking ApoE status with BBB function (45, 46), and pericyte degeneration was strongly associated with BBB abnormalities in the brains of AD patients (30).”
Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease
Xian, X., Pohlkamp, T., Durakoglugil, M. S., Wong, C. H., Beck, J. K., Lane-Donovan, C., Plattner, F., & Herz, J. (2018) · eLife · doi:10.7554/elife.40048 · Cited by 98
“This hypothesis was the initial driver that defined a plethora of surprising functions of LDL receptorrelated proteins (LRPs) in the central and peripheral nervous system (Bal et al., 2013; Beffert et al., 2005; Bell et al., 2012; Choi et al., 2013; Kim et al., 2008; Lane-Donovan and Herz, 2017; Liu et al., 2013; Liu…”
BackgroundThe Blood–Brain Barrier and Its Intercellular Junctions in Age-Related Brain Disorders
Costea, L., Mészáros, Á., Bauer, H., Bauer, H., Traweger, A., Wilhelm, I., Farkas, A. E., & Krizbai, I. A. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20215472 · Cited by 102
Erickson, M. A., Hansen, K. M., & Banks, W. A. (2012) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2012.07.003 · Cited by 102
“Cyclophilin A is also upregulated by ROS, and participates in the vascular inflammatory process by activating NF-kB signaling (Bell et al., 2012; Satoh et al., 2010).”
Astrocytes in the regulation of cerebrovascular functions
Cohen‐Salmon, M., Slaoui, L., Mazaré, N., Gilbert, A., Oudart, M., Alvear‐Perez, R., Elorza‐Vidal, X., Chever, O., & Boulay, A. (2021) · Glia · doi:10.1002/glia.23924 · Cited by 93
“Astro- cytes also induce BBB repair through several mechanisms, such as the release of Shh (Alvarez et al., 2011) and ApoE (Bell et al., 2012).”
BackgroundInfluentialInteractions of Lipids, Lipoproteins, and Apolipoproteins with the Blood-Brain Barrier
Rhea, E. M., & Banks, W. A. (2021) · Pharmaceutical Research · doi:10.1007/s11095-021-03098-6 · Cited by 104
Blood-brain barrier disruption: a culprit of cognitive decline?
Che, J., Sun, Y., Deng, Y., & Zhang, J. (2024) · Fluids and Barriers of the CNS · doi:10.1186/s12987-024-00563-3 · Cited by 111
“This change in BBB permeability is associated with activation of the cyclophilin A (CypA)-MMP-9 pathway in cerebral microvessels [175].”
BackgroundThe blood–brain barrier: a help and a hindrance
Rust, R., Yin, H. R., Buil, B. A., Sagare, A. P., & Kisler, K. (2025) · Brain · doi:10.1093/brain/awaf068 · Cited by 109
“22,187,306 Evidence from stroke models 212,213,307 and models of vascular-induced neurodegeneration 109,308 suggest that BBB breakdown may lead to neuronal and synaptic dysfunction and/or loss, which can be slowed down and is often associated with improved neuronal and synaptic recovery after BBB…”
Self-citationMak, A. C. Y., Pullinger, C. R., Tang, L. F., Wong, J. S., Deo, R. C., Schwarz, J.-M., Gugliucci, A., Movsesyan, I., Ishida, B. Y., Chu, C., et al. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2014.2011 · Cited by 94
Vascular D efects and S pinal C ord H ypoxia in S pinal M uscular A trophy
Somers, E., Lees, R. D., Hoban, K., Sleigh, J. N., Zhou, H., Muntoni, F., Talbot, K., Gillingwater, T. H., & Parson, S. H. (2015) · Annals of Neurology · doi:10.1002/ana.24549 · Cited by 104
Mouse Models to Study the Effect of Cardiovascular Risk Factors on Brain Structure and Cognition
Bink, D. I., Ritz, K., Aronica, E., van der Weerd, L., & Daemen, M. J. A. P. (2013) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2013.140 · Cited by 96
Matrix Metalloproteinases as New Targets in Alzheimer’s Disease: Opportunities and Challenges
Zipfel, P., Rochais, C., Baranger, K., Rivera, S., & Dallemagne, P. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00352 · Cited by 94
de Oliveira, J., Engel, D. F., de Paula, G. C., Santos, D. B., Lopes, J. B., Farina, M., Moreira, E. L. G., & Bem, A. F. D. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200541 · Cited by 102
Blood will out: vascular contributions to Alzheimer’s disease
Strickland, S. (2018) · Journal of Clinical Investigation · doi:10.1172/jci97509 · Cited by 97
“Patients with mild cognitive impairment have been shown to have a compromised BBB (115).”
InfluentialGao, P., Jiang, Y., Chen, W., Gu, J., Miao, S., Wang, X., Huang, Y., Jiang, T., Li, Q., Zhou, W., et al. (2023) · Journal of Nanobiotechnology · doi:10.1186/s12951-023-02110-y · Cited by 98
“Endothelial tight junctions serve as physical barrier [10–13], preventing the entry of macromolecules, cells, and harmful substances into the medulla spinalis [14, 15].”
BackgroundThe APOE4 allele shows opposite sex bias in microbleeds and Alzheimer’s Disease of humans and mice
Cacciottolo, M., Christensen, A., Moser, A., Liu, J., Pike, C., Smith, C., LaDu, M., Sullivan, P., Morgan, T., Dolzhenko, E., et al. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.10.010 · Cited by 93
“, 2015) which is increased by APOE4 (Bell et al., 2012) could contribute to preclinical Ab.”
BackgroundAbsolute 10-year risk of dementia by age, sex and APOE genotype: a population-based cohort study
Rasmussen, K. L., Tybjærg-Hansen, A., Nordestgaard, B. G., & Frikke-Schmidt, R. (2018) · Canadian Medical Association Journal · doi:10.1503/cmaj.180066 · Cited by 91
Metadata
- Authors
- Bell, R. D., Winkler, E. A., Singh, I., Sagare, A. P., Deane, R., Wu, Z., Holtzman, D. M., Betsholtz, C., Armulik, A., Sallstrom, J., Berk, B. C., & Zlokovic, B. V.
- Affiliations
- University of Rochester Medicine (US)
- Washington University in St. Louis (US)
- Karolinska Institutet (SE)
- ORCID
- Venue
- Nature
- Published
- 2012-05-16
- Volume
- 485
- Issue
- 7399
- Pages
- 512-516
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4047116
- OpenAlex
- W2031762899
- Cited by
- 1,293
- References
- 35
- Citations by year
- 2026: 77 · 2025: 79 · 2024: 104 · 2023: 98 · 2022: 99 · 2021: 135 · 2020: 116 · 2019: 95 · 2018: 73 · 2017: 76 · 2016: 73 · 2015: 85 · 2014: 76 · 2013: 68 · 2012: 35
- FWCI
- 42.54
- Type
- journal article
- Language
- en
- Update notices
- correction (2023-05-05)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Institute on Aging (R01AG039452, R37AG023084, R37AG13956, R37AG23084, RF1AG039452, R37AG013956)
- National Institute of Neurological Disorders and Stroke (R37NS034467, R01NS034467, R37NS34467)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- APOE ε4, cyclophilin A, blood-brain barrier disruption, cerebrovascular integrity, MMP-9, NF-κB signaling, pericytes, cerebral blood flow, neurovascular dysfunction, Alzheimer's disease, neuroinflammation, cyclosporine, APOE isoforms, neurodegeneration, ApoE-deficient mice
- MeSH terms
- Animals, Apolipoproteins E, Blood-Brain Barrier, Cerebrovascular Circulation, Hippocampus, Humans, Mice, Transgenic, Microcirculation, Neurons, NF-kappa B, Neurodegenerative Diseases, Pericytes, Matrix Metalloproteinase 9, Cyclophilin A, Mice, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2
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