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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.
In the citing paper
“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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In the citing paper
“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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In the citing paper
“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.
In the citing paper
“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
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
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]
The cited source says what the claim attributes to it.
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]
The cited source says what the claim attributes to it.
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]
The cited source says what the claim attributes to it.
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]
The cited source says what the claim attributes to it.
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]
The cited source says what the claim attributes to it.
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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“…shown that lack of murine Apoe and expression of APOE4 gene, a major genetic risk factor for AD, but not APOE2 and APOE3 , leads to BBB dysfunction by activating a proin fl ammatory cyclophilin A (CypA) – nuclear factor-κ B – matrix-metalloproteinase-9 pathway in mouse pericytes (Bell et al., 2012).”
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“Studies using various transgenic mouse models show that astrocyte-secreted APOE4, but not APOE3 or APOE2, is associated with increased blood–brain barrier leak and increased neuronal degeneration (Bell et al. 2012) in a manner that may be relevant to Alzheimer’s disease pathology (Zlokovic 2011).”
BackgroundFunction and therapeutic value of astrocytes in neurological diseases
Lee, H.-G., Wheeler, M. A., & Quintana, F. J. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00390-x · Cited by 662
Age, APOE and sex: triad of risk of Alzheimer’s disease.
Riedel, B. C., Thompson, P. M., & Brinton, R. D. (2016) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2016.03.012 · Cited by 627
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“Microvascular capillary length was quantified as the length of lectin-positive endothelial profiles (<6 mm in diameter) determined using the ImageJ plug-in length analysis tool from 15 images per specimen derived from five randomly selected fields in the cortex (420mm 420 mm) per section from three non-adjacent ( 100…”
BackgroundMethodResultInfluentialSelf-citationApoE and Aβ in Alzheimer’s Disease: Accidental Encounters or Partners?
Kanekiyo, T., Xu, H., & Bu, G. (2014) · Neuron · doi:10.1016/j.neuron.2014.01.045 · Cited by 608
RETRACTED ARTICLE: Pericyte loss influences Alzheimer-like neurodegeneration in mice
Sagare, A. P., Bell, R. D., Zhao, Z., Ma, Q., Winkler, E. A., Ramanathan, A., & Zlokovic, B. V. (2013) · Nature Communications · doi:10.1038/ncomms3932 · Cited by 589
Self-citationRetractedThe dynamic blood–brain barrier
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Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease
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Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease
Nelson, A. R., Sweeney, M. D., Sagare, A. P., & Zlokovic, B. V. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.12.016 · Cited by 559
“In agreement with these findings, APOE4 transgenic mice exhibit activation of the CypA-NFκB-MMP-9 pathway in pericytes that was demonstrated to result in degradation of BBB tight junction and basement membrane proteins causing BBB disruption [35].”
BackgroundSelf-citationSengillo, J. D., Winkler, E. A., Walker, C. T., Sullivan, J. S., Johnson, M., & Zlokovic, B. V. (2013) · Brain Pathology · doi:10.1111/bpa.12004 · Cited by 553
“This all may potentially contribute to an increase in BBB permeability, allowing neurotoxic, plasma-derived proteins to accumulate in the brain parenchyma (4, 29), and, in some cases, precede and/or even cause neurodegeneration (4, 5, 29, 36).”
BackgroundMethodInfluentialSelf-citationA Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward
Belloy, M. E., Napolioni, V., & Greicius, M. D. (2019) · Neuron · doi:10.1016/j.neuron.2019.01.056 · Cited by 570
Vascular contributions to cognitive impairment and dementia including Alzheimer's disease
Snyder, H. M., Corriveau, R. A., Craft, S., Faber, J. E., Greenberg, S. M., Knopman, D., Lamb, B. T., Montine, T. J., Nedergaard, M., Schaffer, C. B., et al. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.10.008 · Cited by 603
“Irrespective of mechanism, BBB disruption exposes the brain parenchyma to potentially neurotoxic blood proteins, e.g. thrombin, fibrin, plasmin, and hemoglobin, and the iron from lysed erythrocytes (i.e., siderosis) [42].”
BackgroundInfluentialFibrinogen in neurological diseases: mechanisms, imaging and therapeutics
Petersen, M. A., Ryu, J. K., & Akassoglou, K. (2018) · Nature reviews. Neuroscience · doi:10.1038/nrn.2018.13 · Cited by 527
Disruption of astrocyte–vascular coupling and the blood–brain barrier by invading glioma cells
Watkins, S., Robel, S., Kimbrough, I. F., Robert, S. M., Ellis‐Davies, G. C. R., & Sontheimer, H. W. (2014) · Nature Communications · doi:10.1038/ncomms5196 · Cited by 582
Glial influence on the blood brain barrier
Alvarez, J. I., Katayama, T., & Prat, A. (2013) · Glia · doi:10.1002/glia.22575 · Cited by 577
“However, divergent data provided by a more recent study showed that astrocyte-secreted ApoE4 is able to disrupt BBB integrity by regulating the activation of the cyclophilin A–NF-kB–MMP-9 pathway in pericytes (Bell et al., 2012) (Fig.”
BackgroundKang, L., Yu, H., Yang, X., Zhu, Y., Bai, X., Wang, R., Cao, Y., Xu, H., Luo, H., Lu, L., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16191-y · Cited by 554
Physiological blood–brain transport is impaired with age by a shift in transcytosis
Yang, A. C., Stevens, M. Y., Chen, M. B., Lee, D. P., Stähli, D., Gate, D., Contrepois, K., Chen, W., Iram, T., Zhang, L., et al. (2020) · Nature · doi:10.1038/s41586-020-2453-z · Cited by 477
Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain
Kisler, K., Nelson, A. R., Rege, S. V., Ramanathan, A., Wang, Y., Ahuja, A., Lazic, D., Tsai, P. S., Zhao, Z., Zhou, Y., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4489 · Cited by 497
Cyclophilin A: a key player for human disease
Nigro, P., Pompilio, G., & Capogrossi, M. C. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.410 · Cited by 471
“A growing body of evidence suggests oxidative stress involvement in neurodegenerative diseases.84 In addition, many papers showed the contribution of CyPA in oxidative stress mediateddiseases.21,30,32 Recently Bell et al.85 reported the involvement of CyPA in Alzheimer disease.”
BackgroundRhoA/Rho-Kinase in the Cardiovascular System
Shimokawa, H., Sunamura, S., & Satoh, K. (2016) · Circulation Research · doi:10.1161/circresaha.115.306532 · Cited by 468
“Thus, the RhoA/ Rho-kinase signaling pathway is involved in the mechanotransduction mechanism involved in the adherence junction strengthening at EC–EC contacts (Figure 4).(48) This endothelial mechanosensing is required for EC alignment along the flow direction, which contributes to vascular homeostasis.”
BackgroundNeuronal regulation of the blood–brain barrier and neurovascular coupling
Kaplan, L., Chow, B. W., & Gu, C. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-020-0322-2 · Cited by 455
Age-associated Physiological and Pathological Changes at the Blood-Brain Barrier: A Review
Erdő, F., Denes, L., & de Lange, E. (2017) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x16679420 · Cited by 426
“A recent study by Bell et al.94 suggested that CypA is a key target for treating APOE4-mediated neurovascular injury and the resulting neuronal dysfunction and degeneration; indeed, activating a proinflammatory CypA-nuclear factor-jB-MMP-9 pathway in pericytes is associated with increased susceptibility of the BBB to…”
BackgroundInfluentialApolipoprotein e sets the stage: response to injury triggers neuropathology
Mahley, R. W., & Huang, Y. (2012) · Neuron · doi:10.1016/j.neuron.2012.11.020 · Cited by 412
Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance
Zhao, Z., Sagare, A. P., Ma, Q., Halliday, M. R., Kong, P., Kisler, K., Winkler, E. A., Ramanathan, A., Kanekiyo, T., Bu, G., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4025 · Cited by 410
Self-citationPericytes and Neurovascular Function in the Healthy and Diseased Brain
Brown, L. S., Foster, C. G., Courtney, J.-M., King, N. E., Howells, D. W., & Sutherland, B. A. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00282 · Cited by 406
Apolipoprotein E in Alzheimer's Disease: An Update
Yu, J.-T., Tan, L., & Hardy, J. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-014300 · Cited by 394
“…various APOE isoforms differently modulate the components of the innate immune system via multiple signaling pathways, including NF-κB signaling (Bell et al. 2012), p38 MAP kinase signaling (Baitsch et al. 2011), JNK signaling (Pocivavsek et al. 2009), and endoplasmic reticulum stress…”
BackgroundInfluentialPericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss
Nikolakopoulou, A. M., Montagne, A., Kisler, K., Dai, Z., Wang, Y., Huuskonen, M. T., Sagare, A. P., Lazić, D., Sweeney, M. D., Kong, P., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0434-z · Cited by 386
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“Several published studies have identified astrocyte-released effector molecules that can contribute to development of the BBB phenotype including members of the hedgehog family,(11) angiotensin II,(12) and/or apolipoprotein E (APOE)/ lipoprotein receptor-related protein 1 (LRP1) signaling.(13) Similarly, pericyte-defi…”
BackgroundApolipoprotein E in lipoprotein metabolism, health and cardiovascular disease
Marais, A. D. (2019) · Pathology · doi:10.1016/j.pathol.2018.11.002 · Cited by 382
Seven sirtuins for seven deadly diseases ofaging
Morris, B. J. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.10.525 · Cited by 386
“Unlike APOE3, APOE4 is unable to prevent inflammation in pericytes and the consequent disruption of the blood–brain barrier leads to leakage of bloodborne molecules that are toxic to neurons [418].”
BackgroundAstrocytic laminin regulates pericyte differentiation and maintains blood brain barrier integrity
Yao, Y., Chen, Z.-L., Norris, E. H., & Strickland, S. (2014) · Nature Communications · doi:10.1038/ncomms4413 · Cited by 357
Apolipoprotein E, Receptors, and Modulation of Alzheimer’s Disease
Zhao, N., Liu, C.-C., Qiao, W., & Bu, G. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.03.003 · Cited by 370
Blood–spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis
Winkler, E. A., Sengillo, J. D., Sullivan, J. S., Henkel, J. S., Appel, S. H., & Zlokovic, B. V. (2013) · Acta Neuropathologica · doi:10.1007/s00401-012-1039-8 · Cited by 354
Self-citationMontagne, A., Nikolakopoulou, A. M., Zhao, Z., Sagare, A. P., Si, G., Lazic, D., Barnes, S. R., Daianu, M., Ramanathan, A., Go, A., et al. (2018) · Nature Medicine · doi:10.1038/nm.4482 · Cited by 344
Self-citationRetractedAPOE ε4: The most prevalent yet understudied risk factor for Alzheimer's disease
Michaelson, D. M. (2014) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.06.015 · Cited by 331
“In addition, apoE4 increases the susceptibility of the blood brain barrier (BBB) to injury [52].”
BackgroundInoue, Y., Shue, F., Bu, G., & Kanekiyo, T. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00640-5 · Cited by 380
“Accumulating evidence demonstrates that APOE-ε4 leads to BBB dysfunction [265] where the mechanism is likely mediated by excess activation of cyclophilin A-MMP9 pathway in pericytes [266].”
BackgroundWang, C., Xiong, M., Gratuze, M., Bao, X., Shi, Y., Andhey, P. S., Manis, M., Schroeder, C., Yin, Z., Madore, C., et al. (2021) · Neuron · doi:10.1016/j.neuron.2021.03.024 · Cited by 334
Self-citationFocused ultrasound-mediated drug delivery through the blood–brain barrier
Burgess, A., Shah, K., Hough, O., & Hynynen, K. (2015) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2015.1028369 · Cited by 332
“Finally, astrocyte-derived proteins, such as ApoE4, can activate a proinflammatory pathway, leading to chronic BBB opening [31].”
Background16S rRNA Next Generation Sequencing Analysis Shows Bacteria in Alzheimer’s Post-Mortem Brain
Emery, D. C., Shoemark, D. K., Batstone, T. E., Waterfall, C. M., Coghill, J. A., Cerajewska, T. L., Davies, M., West, N. X., & Allen, S. J. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00195 · Cited by 317
“Additionally, the integrity of the blood-brainbarrier (BBB) diminishes, partly with age, increased cytokine load and in the context of apolipoprotein E4 (ApoE4; Bell et al., 2012).”
BackgroundApoE Cascade Hypothesis in the pathogenesis of Alzheimer’s disease and related dementias
Martens, Y. A., Zhao, N., Liu, C.-C., Kanekiyo, T., Yang, A. J., Goate, A. M., Holtzman, D. M., & Bu, G. (2022) · Neuron · doi:10.1016/j.neuron.2022.03.004 · Cited by 316
Self-citationXiao, X., Huang, S., Chen, S., Wang, Y., Sun, Q., Xu, X., & Li, Y. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02148-6 · Cited by 347
“Astrocytes can also increase BBB permeability through various mechanisms, including the production of apolipoprotein E (APOE) and inhibition of the cyclophilin A (CYA)–NF-κB–matrix metalloproteinase 9 (MMP9) pathway in pericytes [74].”
BackgroundBlood-brain barrier regulation in psychiatric disorders
Kealy, J., Greene, C., & Campbell, M. (2018) · Neuroscience Letters · doi:10.1016/j.neulet.2018.06.033 · Cited by 318
“plexes, increasing BBB permeability [263].”
APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease
Li, Z., Shue, F., Zhao, N., Shinohara, M., & Bu, G. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00413-4 · Cited by 306
“Moreover, the association between APOE*ε4 and BBB breakdown in humans is independent of Aβ and tau pathologies [139], but appears to be caused by functional changes of pericytes [137, 139, 140].”
BackgroundResultApoE attenuates unresolvable inflammation by complex formation with activated C1q
Yin, C., Ackermann, S., Ma, Z., Mohanta, S. K., Zhang, C., Li, Y., Nietzsche, S., Westermann, M., Peng, L., Hu, D., et al. (2019) · Nature Medicine · doi:10.1038/s41591-018-0336-8 · Cited by 305
Hammer, C., Stepniak, B., Schneider, A., Papiol, S., Tantra, M., Begemann, M., Sirén, A.-L., Pardo, L. A., Sperling, S., Mohd Jofrry, S., et al. (2014) · Molecular Psychiatry · doi:10.1038/mp.2013.110 · Cited by 342
A journey into the brain: insight into how bacterial pathogens cross blood–brain barriers
Coureuil, M., Lécuyer, H., Bourdoulous, S., & Nassif, X. (2017) · Nature Reviews Microbiology · doi:10.1038/nrmicro.2016.178 · Cited by 305
Ketogenic diet enhances neurovascular function with altered gut microbiome in young healthy mice
Ma, D., Wang, A. C., Parikh, I. J., Green, S. J., Hoffman, J. D., Chlipala, G. E., Murphy, M. P., Sokola, B. S., Bauer, B., Hartz, A. M. S., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-25190-5 · Cited by 315
Apolipoprotein E: Structural Insights and Links to Alzheimer Disease Pathogenesis
Chen, Y., Strickland, M. R., Soranno, A., & Holtzman, D. M. (2021) · Neuron · doi:10.1016/j.neuron.2020.10.008 · Cited by 298
“Due to its pleiotropic effects, ApoE may influence AD in other ways, including effects on the blood-brain-barrier, synaptic plasticity, and possibly other mechanisms (Bell et al., 2012; Liu et al., 2013).”
Self-citationApoE facilitates the microglial response to amyloid plaque pathology
Ulrich, J. D., Ulland, T. K., Mahan, T. E., Nyström, S., Nilsson, K. P., Song, W. M., Zhou, Y., Reinartz, M., Choi, S., Jiang, H., et al. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20171265 · Cited by 297
“However, beyond its effect on amyloid, apoE also influences diverse processes in the brain, such as synaptogenesis, phagocytosis, BBB function, and microglial activation (Mauch et al., 2001; Bell et al., 2012; Butovsky et al., 2015; Chung et al., 2016; Krasemann et al., 2017; Shi et al., 2017).”
Self-citationShinohara, M., Tachibana, M., Kanekiyo, T., & Bu, G. (2017) · Journal of Lipid Research · doi:10.1194/jlr.r075796 · Cited by 297
“LRP1 is abundantly expressed in pericytes at the BBB, where apoE prevents the activation of the proinflammatory cyclophilin A-nuclear factor light-chain-enhancer of activated B cells-matrix metallopeptidase 9 (CypA-NFB-MMP9) pathway through LRP1 (155).”
BackgroundHealthy aging and the blood–brain barrier
Banks, W. A., Reed, M. J., Logsdon, A. F., Rhea, E. M., & Erickson, M. A. (2021) · Nature Aging · doi:10.1038/s43587-021-00043-5 · Cited by 310
Ma, Q., Zhao, Z., Sagare, A. P., Wu, Y., Wang, M., Owens, N. C., Verghese, P. B., Herz, J., Holtzman, D. M., & Zlokovic, B. V. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0286-0 · Cited by 281
Self-citationCerebral small vessel disease: Capillary pathways to stroke and cognitive decline
Østergaard, L., Engedal, T. S., Moreton, F. C., Hansen, M. B., Wardlaw, J. M., Dalkara, T., Markus, H. S., & Muir, K. W. (2015) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x15606723 · Cited by 290
“Pericytes undergo degeneration when exposed to certain Ab types in vitro,(62,63) and although the role of pericytes in the pathogenesis of cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD) remains poorly understood, evidence from Ab transgenic mice and in vitro models suggest they may be involved in neuro…”
BackgroundInnate Immunity in the CNS: Redefining the Relationship between the CNS and Its Environment
Lampron, A., ElAli, A., & Rivest, S. (2013) · Neuron · doi:10.1016/j.neuron.2013.04.005 · Cited by 291
Kanekiyo, T., & Bu, G. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00093 · Cited by 281
“Furthermore, apoE4 activates the cyclophilin A-MMP9 pathway through LRP1 in pericytes, leading to damages of BBB integrity (Bell et al., 2012).”
BackgroundHarris, S. A., & Harris, E. A. (2015) · Journal of Alzheimer's Disease · doi:10.3233/jad-142853 · Cited by 279
The Pericyte: A Forgotten Cell Type with Important Implications for A lzheimer's Disease?
Winkler, E. A., Sagare, A. P., & Zloković, B. V. (2014) · Brain Pathology · doi:10.1111/bpa.12152 · Cited by 284
Self-citationFernández-Calle, R., Konings, S. C., Frontiñán-Rubio, J., García-Revilla, J., Camprubí-Ferrer, L., Svensson, M., Martinson, I., Boza-Serrano, A., Venero, J. L., Nielsen, H. M., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00566-4 · Cited by 278
Clearance of cerebral Aβ in Alzheimer’s disease: reassessing the role of microglia and monocytes
Zuroff, L. R., Daley, D. A., Black, K. L., & Koronyo‐Hamaoui, M. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2463-7 · Cited by 292
Govindpani, K., McNamara, L. G., Smith, N. R., Vinnakota, C., Waldvogel, H. J., Faull, R. L. M., & Kwakowsky, A. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8050651 · Cited by 281
“Meanwhile, unlike APOE3, APOE4 appears not to suppress this pathway, resulting in greater cerebrovascular injury [220].”
BackgroundThe impact of chronic blood–brain barrier breach on intracortical electrode function
Saxena, T. K., Karumbaiah, L., Gaupp, E. A., Patkar, R., Patil, K., Betancur, M. I., Stanley, G. B., & Bellamkonda, R. V. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2013.03.007 · Cited by 270
“Since MMP-2 is associated with wound healing and angiogenesis [20,23], we quantified the collagen IV positive blood vessels [21] around electrode implant sites and found that microwire electrodes had a significantly (p < 0.”
BackgroundRole of the Blood-Brain Barrier in Central Nervous System Insulin Resistance
Rhea, E. M., & Banks, W. A. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00521 · Cited by 272
“At the BBB, astrocytes help provide maintenance and repair support through release of several effector molecules (Wosik et al., 2007; Alvarez et al., 2011; Bell et al., 2012).”
BackgroundBridging barriers: a comparative look at the blood–brain barrier across organismsPreprint
O’Brown, N. M., Pfau, S. J., & Gu, C. (2018) · Genes & Development · doi:10.1101/gad.309823.117 · Cited by 267
“Finally, recent studies have sought to determine the role of pericytes in the pathology of neurodegenerative diseases (Bell et al. 2010, 2012; Kisler et al. 2017a), finding that pericyte dysfunction typically precedes neurodegeneration in mouse models.”
BackgroundCholesterol: its regulation and role in central nervous system disorders
Orth, M., & Bellosta, S. (2012) · Cholesterol · doi:10.1155/2012/292598 · Cited by 339
“In the absence of murine apoE, human apoE4 but not apoE3 or apoE2 leads to BBB breakdown by activating the proinflammatory cyclophilin A in pericytes [208].”
BackgroundEmerging Roles for the Immune System in Traumatic Brain Injury
McKee, C. A., & Lukens, J. R. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00556 · Cited by 277
“Moreover, transgenic overexpression of APOEε4 in mice was also found to cause worsened brain pathology, BBB breakdown, and neurological impairments following brain injury (159, 160).”
Background
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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