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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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“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]
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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]
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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Peripheral Pathways to Neurovascular Unit Dysfunction, Cognitive Impairment, and Alzheimer’s Disease
Nelson, A. R. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.858429 · Cited by 24
Calcetas, A. T., Thomas, K. R., Edmonds, E. C., Holmqvist, S. L., Edwards, L., Bordyug, M., Delano‐Wood, L., Brickman, A. M., Bondi, M. W., Bangen, K. J., et al. (2022) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2022.06.002 · Cited by 22
Dementia risk and dynamic response to exercise: A non-randomized clinical trial
Vidoni, E. D., Morris, J. K., Palmer, J. A., Li, Y., White, D., Kueck, P. J., John, C. S., Honea, R. A., Lepping, R. J., Lee, P., et al. (2022) · PLoS ONE · doi:10.1371/journal.pone.0265860 · Cited by 22
“Apolipoprotein E plays an integral role in maintenance of cerebrovascular health and may interact with aging processes to mediate benefits of long-term exercise interventions on brain health [26, 27].”
BackgroundVascular endothelial cells: a fundamental approach for brain waste clearance
Wei, H., Jiang, H., Zhou, Y., Xiao, X., Zhou, C., & Ji, X. (2022) · Brain · doi:10.1093/brain/awac495 · Cited by 20
Li, M., Sun, Z., Sun, H., Zhao, G., Leng, B., Shen, T., Xue, S., Hou, H., Li, Z., & Zhang, J. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-01153-x · Cited by 23
Yan, S., Si, Y., Zhou, W., Cheng, R., Wang, P., Wang, D., Ding, W., Shi, W., Jiang, Q., Yang, F., et al. (2023) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2023.106801 · Cited by 24
Alzheimer’s disease is an inherent, natural part of human brain aging: an integrated perspective
Ferrer, I. (2022) · Free Neuropathology · doi:10.17879/freeneuropathology-2022-3806 · Cited by 25
Feng, L., Li, Y., Lin, M., Xie, D., Luo, Y., Zhang, Y., He, Z., Gong, Q., Zhu, Y. Z., & Gao, J. (2023) · British Journal of Pharmacology · doi:10.1111/bph.16239 · Cited by 22
“Recent studies have found that the proinflammatory CypA/NF-κ B/ MMP9 pathway controls integrity of the BBB, which requires APOE4 (Bell et al., 2012).”
BackgroundFaraji, P., Kühn, H., & Ahmadian, S. (2024) · Journal of Molecular Neuroscience · doi:10.1007/s12031-024-02224-4 · Cited by 25
“…increases the risk of vascular dementia and atherosclerosis (Mahley et al. 2009; Rohn 2014) In vivo APOE4 carriers show cerebrovascular dysfunction (Bell et al. 2012; Tai et al. 2016) In vivo Clinical trials APOE4 induces accumulation of Aβ, fibrin, and fibrinogen in the neuro-vasculature of AD…”
Backgroundder Donckt, C. V., Roth, L., Vanhoutte, G., Blockx, I., Bink, D. I., Ritz, K., Pintelon, I., Timmermans, J., Bauters, D., Martinet, W., et al. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.03.023 · Cited by 21
“Compared to those in regular ApoE / mice, atherosclerotic plaques in ApoE / Fbn1 mice are characterized by increased expression of the pro-inflammatory cytokines interleukin-1 beta (IL-1b) and tumor necrosis factor-alpha (TNF-a) and the matrix metalloproteinases (MMP)-2 and -9, which are known to affect BBB integrity…”
BackgroundLee, J., Yanckello, L. M., Ma, D., Hoffman, J. D., Parikh, I. J., Thalman, S. W., Bauer, B., Hartz, A. M. S., Hyder, F., & Lin, A. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00225 · Cited by 20
“Young, presymptomatic APOE4 mice have significantly lower CMRglc and CBF, as well as increased BBB leakage compared to the wild-type (WT) non-APOE4 mice (Bell et al., 2012; Lin et al., 2017a).”
BackgroundJoseph, C. R. (2020) · Biomedicines · doi:10.3390/biomedicines8070228 · Cited by 20
“as established did they appear and ith- it other findings of breached vascular integrity [31].”
BackgroundInfluentialCooperation between neurovascular dysfunction and Aβ in Alzheimer’s disease
Wang, N., Yang, X., Zhao, Z., Liu, D., Wang, X., Tang, H., Zhong, C., Chen, X., Chen, W. K., & Meng, Q. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2023.1227493 · Cited by 22
“In transgenic mice designed to target mouse with human APOE4 gene, decreased CBF and vascular dysfunction were similarly observed, and vascular abnormalities in animals expressing APOE4 occurred before neural and synaptic problems (Bell et al., 2012).”
BackgroundNeural Regulation of Vascular Development: Molecular Mechanisms and Interactions
Zhang, Y., Shen, X., Deng, S., Chen, Q., & Xu, B. (2024) · Biomolecules · doi:10.3390/biom14080966 · Cited by 21
“Apolipoprotein E (APOE) expressed by astrocytes binds to low-density lipoprotein receptor-related protein-1 (LRP-1) on pericytes or endothelial cells, regulating the expression of matrix metalloproteinase-9 (MMP-9) and BBB function [102].”
BackgroundThe blood–brain barrier as a treatment target for neurodegenerative disorders
Rust, R., Sagare, A. P., Zhang, M., Zloković, B. V., & Kisler, K. (2025) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2025.2480654 · Cited by 21
“Furthermore, the E4 variant of apolipoprotein E ( APOE4 ), the strongest genetic risk factor for AD, has been shown to accelerate BBB disruption and loss of pericytes [32–35], the BBB-associated cells that maintain BBB integrity (Figure 1(a)) [36–39].”
InfluentialSelf-citationVellucci, L., Mazza, B., Barone, A., Nasti, A., Simone, G. D., Iasevoli, F., & de Bartolomeis, A. (2025) · Biomolecules · doi:10.3390/biom15050615 · Cited by 23
“…E (APOE), which is relevant to maintaining the BBB structure via the suppression of cyclophilin A (CYPA), NF-κ B, and metalloproteinase 9 (MMP9) signaling in pericytes, thereby counteracting APOE4-associated BBB breakdown [171,172]; (iii) maintaining extracellular potassium levels through Kir1.”
McInerney, M. P., Short, J. L., & Nicolazzo, J. A. (2017) · The AAPS Journal · doi:10.1208/s12248-017-0077-5 · Cited by 20
Age, sex, and cerebral microbleeds in EFAD Alzheimer disease mice
Cacciottolo, M., Morgan, T. E., & Finch, C. E. (2021) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2021.02.020 · Cited by 20
Zhang, Y., Zhao, B., Lai, Q., Li, Q., Tang, X., Zhang, Y., Pan, Z., Gao, Q., & Zhong, Z. (2022) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x221078065 · Cited by 20
Wang, Y., Kisler, K., Nikolakopoulou, A. M., Fernández, J. A., Griffin, J. H., & Zloković, B. V. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.841916 · Cited by 20
Gong, M., & Jia, J. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.949129 · Cited by 20
“Moreover, treating APOE ε4 mice with low doses of cyclosporine was shown to eliminate BBB damage, indicating that the change in CyPA on the BBB is reversible, and CyPA may be a therapeutic target that causes BBB destruction (Bell et al., 2012; Montagne et al., 2021).”
BackgroundCellular junction dynamics and Alzheimer’s disease: a comprehensive review
Asghari, K., Niknam, Z., Mohammadpour-Asl, S., & Chodari, L. (2024) · Molecular Biology Reports · doi:10.1007/s11033-024-09242-w · Cited by 20
“…proteins, including claudin 5, ZO-1, and occludin, induced by ApoE, is associated with reduced levels of endothelial tight junction proteins claudin-5 and occludin in AD brains, which are independently correlated with increased levels of soluble tau, insoluble p-tau, and ApoE [151, 152, 158 ].”
Hsp90-Binding Immunophilins As A Potential New Platform for Drug Treatment
Erlejman, A. G., Lagadari, M., & Galigniana, M. D. (2013) · Future Medicinal Chemistry · doi:10.4155/fmc.13.7 · Cited by 20
“CyPA was also related to Alzheimer’s disease via the apolipoprotein E pathway that controls cerebrovascular integrity [87] .”
The blood-brain interface: a culture change
Galea, I., & Perry, V. H. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.10.014 · Cited by 20
Piccarducci, R., Daniele, S., Fusi, J., Chico, L., Baldacci, F., Siciliano, G., Bonuccelli, U., Franzoni, F., & Martini, C. (2019) · Antioxidants · doi:10.3390/antiox8110538 · Cited by 20
“Concomitantly, ApoE ε4 alters the permeability of the blood–brain barrier (BBB), reducing the control of the passage of molecules, as Aβ peptide, from the brain to blood and vice versa [5].”
BackgroundHu, Y., Meuret, C., Martinez, A., Yassine, H. N., & Nedelkov, D. (2021) · Journal of Lipid Research · doi:10.1194/jlr.ra120000919 · Cited by 18
“It has been shown that lipoprotein bound apoE4 does not preferentially bind to LRP1 like the other two apoE isoforms (E2 and E3), which was suggested to affect Aβ clearance (75, 76).”
BackgroundZhang, Q., Song, Q., Gu, X., Zheng, M., Wang, A., Jiang, G., Huang, M., Chen, H., Qiu, Y., Bo, B., et al. (2021) · Advanced Science · doi:10.1002/advs.202001918 · Cited by 19
Marques, D., Moura-Louro, D., Silva, I. P., Matos, S., dos Santos, C. N., & Figueira, I. (2024) · Neurochemistry International · doi:10.1016/j.neuint.2024.105836 · Cited by 21
“…and synaptic dysfunction; subsequently, it was reported that the blockade of the CypA-MMP9 pathway in ApoE ε 4 knock-in mice rectified BBB ’ s integrity, by the re-expression of several TJs and AJs proteins, allowing for the restoration of neuronal and synaptic functions (Bell et al., 2012).”
BackgroundThe evolving pathophysiology of TBI and the advantages of temporally-guided combination therapies
Zima, L. A., Moore, A. N., Smolen, P. D., Kobori, N., Noble, B., Robinson, D., Hood, K. N., Homma, R., Mamun, A. A., Redell, J. B., et al. (2024) · Neurochemistry International · doi:10.1016/j.neuint.2024.105874 · Cited by 21
“Similarly, ApoE3 released by A2 astrocytes functions to reduce BBB permeability (Bell et al., 2012).”
BackgroundCyclophilin A: promising target in cancer therapy
Jin, S., Zhang, M., & Qiao, X. (2024) · Cancer Biology & Therapy · doi:10.1080/15384047.2024.2425127 · Cited by 19
García‐Martínez, T., Gornatti, D. G., Ortiz, M., Cañellas, G., Heine‐Suñer, D., & Vives-Bauzá, C. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26051886 · Cited by 20
“This prevents the degradation of TJ and BM proteins, protecting the BBB, whereas ApoE4 lacks this protective effect [69].”
Gläser, E., Kilimann, I., Platen, M., Hoffmann, W. U., Brosseron, F., Büerger, K., Coenjaerts, M., Düzel, E., Ewers, M., Fließbach, K., et al. (2025) · Alzheimer s Research & Therapy · doi:10.1186/s13195-025-01785-9 · Cited by 19
The evolution of microglia replacement: A new paradigm for CNS disease therapy
Rao, Y., Bai, Y., Li, X., Du, B., & Peng, B. (2025) · Cell stem cell · doi:10.1016/j.stem.2025.10.014 · Cited by 25
Pierzchlińska, A., Kwaśniak-Butowska, M., Sławek, J. W., Droździk, M., & Białecka, M. A. (2021) · Molecules · doi:10.3390/molecules26061523 · Cited by 18
You, M., Zhou, X., Yin, W., Wan, K., Zhang, W., Li, C., Li, M., Zhu, W., Zhu, X., & Sun, Z. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.778123 · Cited by 19
Platelet-derived growth factor-BB and white matter hyperintensity burden in APOE4 carriers
Kapoor, A., & Nation, D. A. (2022) · Cerebral Circulation - Cognition and Behavior · doi:10.1016/j.cccb.2022.100131 · Cited by 19
“This further triggers the proinflammatory cyclophilin A–matrixmetalloproteinase-9 (CypA–MMP9) pathway in brain pericytes, leading to pericyte injury, MMP-9 mediated blood-brain barrier breakdown and ultimately, neuronal dysfunction [10,14,15].”
BackgroundSaiyasit, N., Butlig, E.-A. R., Chaney, S. D., Traylor, M. K., Hawley, N. A., Randall, R. B., Bobinger, H. V., Frizell, C. A., Trimm, F., Crook, E. D., et al. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.915405 · Cited by 22
Trivedi, A. A., Zhang, H. M., Ekeledo, A., Lee, S., Werb, Z., Plant, G. W., & Noble‐Haeusslein, L. J. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.07.018 · Cited by 19
“In transgenic mice expressing APOE4, a model of Alzheimer’s disease, increased MMP-9 activity leads to breakdown of tight junction and basement membrane proteins, resulting in diminished pericyte coverage (Bell et al., 2012; Halliday et al., 2015).”
BackgroundTranscriptional regulation of APP by apoE: To boldly go where no isoform has gone before
Lee, L. C., Goh, M. Q. L., & Koo, E. H. (2017) · BioEssays · doi:10.1002/bies.201700062 · Cited by 20
“Disruption of the BBB in apoE4 and apoE-KO was rescued either by the genetic ablation of CypA or inhibiting CypA’s action with cyclosporine A treatment [60].”
BackgroundFu, L., Jiang, G., Weng, H., Dick, G. M., Chang, Y.-Z., & Kassab, G. S. (2019) · Brain Pathology · doi:10.1111/bpa.12759 · Cited by 20
Associations of APOE e2 genotype with cerebrovascular pathology: a postmortem study of 1275 brains
Goldberg, T. E., Huey, E. D., & Devanand, D. P. (2021) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp-2020-323746 · Cited by 19
Luckey, A. M., Robertson, I. H., LAWLOR, B. A., Mohan, A., & Vanneste, S. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210404 · Cited by 24
“Mice studies have linked APOE to BBB dysfunction via (cid:2) 4 alleles’ conduciveness for vascular atrophy resulting in increasing permeability and reducing cerebral blood flow [107, 108].”
Hu, H., Wan, S., Hu, Y., Wang, Q., Li, H., & Zhang, N. (2025) · Annals of Medicine · doi:10.1080/07853890.2024.2445194 · Cited by 20
“This genotype activates the ceramide A–NFκB–metalloproteinase-9 pathway, leading to compromised BBB integrity [129] and thereby disrupting the IPAD pathway for Aβ clearance.”
Abikenari, M. A., Sjöholm, M., Liu, J., Nageeb, G., Ha, J. H., Wu, J. Y., Ren, A. L., Sayadi, J. J., Lim, J., Cho, K. B., et al. (2025) · Frontiers in Physics · doi:10.3389/fphy.2025.1723329 · Cited by 20
“…shape leukocyte adhesion and diapedesis; astrocytic SHH suppresses endothelial ICAM-1, limiting immune entry, whereas NF-κB/STAT3-driven reactive astrogliosis elevates cytokines (IL-6, TNF-α), MMPs, and NO, loosening junctions yet not necessarily improving effector T-cell trafficking [7, 25, 26].”
den Hoedt, S., Crivelli, S. M., Leijten, F. P. J., Losen, M. H., Stevens, J., Mané-Damas, M., de Vries, H. E., Walter, J., Mirzaian, M., Sijbrands, E. J. G., et al. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.765252 · Cited by 19
“In mice, deletion of Apoe or replacement with human APOE4 leads to a dysfunctional cerebrovascular unit (Mulder et al., 2001; Bell et al., 2012), which may affect trafficking of lipids, including sphingolipids, across the blood– brain barrier.”
BackgroundAPOE and Cerebral Small Vessel Disease Markers in Patients With Intracerebral Hemorrhage
Hostettler, I. C., Seiffge, D. J., Wong, A., Ambler, G., Wilson, D., Shakeshaft, C., Banerjee, G., Sharma, N., Jäger, H. R., Cohen, H., et al. (2022) · Neurology · doi:10.1212/wnl.0000000000200851 · Cited by 20
Evidence of emerging BBB changes in mid‐age apolipoprotein E epsilon‐4 carriers
Alruwais, N. M., Rusted, J. M., Tabet, N., & Dowell, N. G. (2022) · Brain and Behavior · doi:10.1002/brb3.2806 · Cited by 17
“To date, most BBB studies have been on murine models (Bell et al., 2012; Daneman et al., 2010) or human postmortem individuals (Sengillo et al., 2013; Toledo et al., 2013), but in a seminal study, Montagne et al. (2015) reported findings from a cohort of non-cognitively impaired (NCI) and mild…”
BackgroundLiu, X., Xiu, C., Zhao, N., Geng, F., Zhu, M., & Ren, Q. (2024) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.13704 · Cited by 20
Bhat, N. R. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-150098 · Cited by 18
“A proposed mechanism for the toxicity of Apo E4 on the cerebrovascular system involves activation of a proinflammaory cyclophyllin Amediated pathway in pericytes leading to BBB breakdown (60).”
Novel roles of oligodendrocyte precursor cells in the developing and damaged brain
Maki, T. (2017) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12358 · Cited by 18
Independent value added by diffusion MRI for prediction of cognitive function in older adults
Scott, J. A., Tosun, D., Braskie, M. N., Maillard, P., Thompson, P. M., Weiner, M. W., DeCarli, C. S., & Carmichael, O. T. (2017) · NeuroImage Clinical · doi:10.1016/j.nicl.2017.01.026 · Cited by 20
“Impaired clearance of amyloid (Rincon and Wright, 2014), damaged blood brain barrier (Farrall and Wardlaw, 2009; Bell et al., 2012), and chronic inflammation (Greer, 2002; Jin et al.”
Microphysiological Neurovascular Barriers to Model the Inner Retinal Microvasculature
Maurissen, T. L., Pavlou, G., Bichsel, C. A., Villaseñor, R., Kamm, R. D., & Ragelle, H. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12020148 · Cited by 20
“Since developing vessels in the retina are leaky despite the presence of astrocytes [62], and astrocytes are not present in the early stages of brain development [75], they are not likely play a key role in initial barrier formation, but rather in barrier maintenance through secreted factors [57,76,77].”
BackgroundEisenbaum, M., Pearson, A., Ortiz, C., Koprivica, M., Cembran, A., MULLAN, M. J., Crawford, F., Ojo, J. O., & Bachmeier, C. J. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114702 · Cited by 18
Zhou, B., Li, J., Wu, A., Wang, X., Cheng, L., Yang, G., Gao, D., & Zhu, C. (2025) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2025.1587986 · Cited by 18
“A study (Bell et al., 2012) indicates that APOE4 independently triggers inflammatory cascades, causing neurovascular dysfunction, while APOE3 ameliorates this condition (Ioannou et al., 2019).”
Abikenari, M. A., Ha, J. H., Liu, J., Ren, A. L., Cho, K. B., Lim, J., Kim, L. H., Medikonda, R. T., Choi, J. H., & Lim, M. K. (2025) · Frontiers in Neurology · doi:10.3389/fneur.2025.1668480 · Cited by 18
“For instance, VEGF and APOE secretion by astrocytes increases leakiness of the BBB (68, 69).”
Sex and APOE ɛ4 modify the effect of cardiovascular risk on tau in cognitively normal older adults
Tsiknia, A. A., Reas, E. T., Bangen, K. J., Sundermann, E. E., McEvoy, L. K., Brewer, J. B., Edland, S. D., Banks, S. J., & Initiative, A. D. N. (2022) · Brain Communications · doi:10.1093/braincomms/fcac035 · Cited by 17
Modeling neurotoxin-induced neuroinflammation with chemotherapy
Tolba, M. F., Sedky, N. K., Ali, M. A., & Abdollah, M. R. A. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-89833-1.00049-5 · Cited by 17
Chai, Y. L., Rajeev, V., Poh, L., Selvaraji, S., Hilal, S., Chen, C., Jo, D., Koo, E. H., Arumugam, T. V., & Lai, M. K. P. (2022) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x221146401 · Cited by 17
Xue, Y., Gu, M., Chen, C., Yao, Y., Li, Y., Weng, G., & Gu, Y. (2023) · Molecular Medicine Reports · doi:10.3892/mmr.2023.12972 · Cited by 18
“Furthermore, ApoE is observed to suppress the cyclophillin A/NF‐κB/MMP‐9 pathway through the low density lipoprotein receptor‐related protein 1 receptor to reverse BBB disruption (13).”
BackgroundPlasma MMP-9/TIMP-1 ratio serves as a novel potential biomarker in Alzheimer’s disease
Liu, J., Li, X., & Qu, J. (2023) · Neuroreport · doi:10.1097/wnr.0000000000001952 · Cited by 21
Onos, K. D., Lin, P. B., Pandey, R. S., Persohn, S. A., Burton, C. P., Miner, E. W., Eldridge, K., Kanyinda, J. N., Foley, K. E., Carter, G. W., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13842 · Cited by 17
“One of the many roles of APOE is regulating cerebrovascular integrity, 21 with lack of APOE expression leading to blood-brain barrier (BBB) disruption.”
Vollhardt, A., Frölich, L., Stockbauer, A., Danek, A., Schmitz, C., & Wahl, A.-S. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.106845 · Cited by 18
“Also APOE 4 is associated with BBB disruption and reduced CBF (Bracko et al., 2021; Bell et al., 2012; Sagare et al., 2013; Montagne et al., 2020; Sweeney et al., 2018b; Filippini et al., 2011; Thambisetty et al., 2010; Michels et al., 2016; McKiernan et al., 2020).”
Understanding How Exercise Promotes Cognitive Integrity in the Aging Brain
Laitman, B. M., & John, G. R. (2015) · PLoS Biology · doi:10.1371/journal.pbio.1002300 · Cited by 18
“For example, vascular defects in mice deficient for the AD risk factor, apolipoprotein E (ApoE), or transgenic for the human APOE4 isoform, display vascular defects that precede neuronal dysfunction [9].”
BackgroundResultSlot, R. E. R., Kester, M. I., van Harten, A. C., Jongbloed, W., Bouwman, F. H., Teunissen, C. E., Scheltens, P., van der Flier, W. M., & Veerhuis, R. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.02.017 · Cited by 18
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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