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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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“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
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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]
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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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Citations
Cites
Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders
Zlokovic, B. V. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn3114 · Cited by 2,969
Pericytes regulate the blood–brain barrier
Armulik, A., Genové, G., Mäe, M., Nisancioglu, M. H., Wallgard, E., Niaudet, C., He, L., Norlin, J., Lindblom, P., Strittmatter, K., et al. (2010) · Nature · doi:10.1038/nature09522 · Cited by 2,843
Self-citationSilent Brain Infarcts and the Risk of Dementia and Cognitive Decline
Vermeer, S. E., Prins, N. D., den Heijer, T., Hofman, A., Koudstaal, P. J., & Breteler, M. M. B. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa022066 · Cited by 2,313
Cyclophilin: A Specific Cytosolic Binding Protein for Cyclosporin A
Handschumacher, R. E., Harding, M. W., Rice, J. S., Drugge, R. J., & Speicher, D. W. (1984) · Science · doi:10.1126/science.6238408 · Cited by 1,675
The role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661
Self-citationBrain Infarction and the Clinical Expression of Alzheimer Disease<subtitle>The Nun Study</subtitle>
Snowdon, D. A. (1997) · JAMA: The Journal of the American Medical Association · doi:10.1001/jama.1997.03540340047031 · Cited by 1,590
Bell, R. D., Winkler, E. A., Sagare, A. P., Singh, I., LaRue, B., Deane, R., & Zlokovic, B. V. (2010) · Neuron · doi:10.1016/j.neuron.2010.09.043 · Cited by 1,448
Self-citationWada, K., Tanaka, K., & Nakashima, K. (2011) · PubMed · Cited by 1,132
Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia
Reiman, E. M., Chen, K., Alexander, G. E., Caselli, R. J., Bandy, D., Osborne, D., Saunders, A. M., & Hardy, J. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2635903100 · Cited by 977
Apolipoprotein E in Alzheimer’s disease and other neurological disorders
Verghese, P. B., Castellano, J. M., & Holtzman, D. M. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70325-2 · Cited by 857
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Apolipoprotein E Inhibits Cerebrovascular Pericyte Mobility through a RhoA Protein-mediated Pathway
Casey, C. S., Atagi, Y., Yamazaki, Y., Shinohara, M., Tachibana, M., Fu, Y., Bu, G., & Kanekiyo, T. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.625251 · Cited by 63
“Importantly, recent findings have shown that apoE regulates BBB integrity and cerebral blood flow in an isoform-dependent manner (16, 17).”
BackgroundNew Insight Into the Pathogenesis of Cerebral Small-Vessel Diseases
Müller, K., Courtois, G., Ursini, M. V., & Schwaninger, M. (2017) · Stroke · doi:10.1161/strokeaha.116.012888 · Cited by 63
“For each individual disease, the contribution of TGFβ signaling has to be further defined because there are clearly alternative ways to explain the pathophysiology.(38,75) A basic question is whether TGF-β signaling is overactive or rather”
BackgroundMoores, R., Brilha, S., Schutgens, F., Elkington, P. T., & Friedland, J. S. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00602 · Cited by 65
“TLR signaling is known to induce changes in HDAC expression and activity (33), and our findings are consistent with published evidence of selective changes in macrophage HDAC expression in response to specific inflammatory stimuli (34).”
ResultApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease
Li, Y., Macyczko, J. R., Liu, C.-C., & Bu, G. (2022) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2022.03.011 · Cited by 61
Alzheimer's brains show inter-related changes in RNA and lipid metabolism
Barbash, S., Garfinkel, B. P., Maoz, R., Simchovitz, A., Nadorp, B., Guffanti, A., Bennett, E. R., Nadeau, C., Türk, A., Paul, L., et al. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.06.008 · Cited by 62
Rieker, C., Migliavacca, E., Vaucher, A., Mayer, F. C., Baud, G., Marquis, J., Charpagne, A., Hegde, N., Guignard, L., McLachlan, M. J., et al. (2019) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.118.312261 · Cited by 59
Effects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice
Miranda, A. M., Ashok, A., Chan, R. B., Zhou, B., Xu, Y., McIntire, L. B., Area-Gomez, E., Di Paolo, G., Duff, K. E., Oliveira, T. G., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-01881-6 · Cited by 60
“Indeed, aging has been shown to be associated with blood brain barrier (BBB) breakdown in the hippocampus [93], and BBB leakage is also found to be an early marker of dysfunction in both APOE4 carriers [94] and mice [95].”
BackgroundPericytic Laminin Maintains Blood-Brain Barrier Integrity in an Age-Dependent Manner
Gautam, J., Cao, Y., & Yao, Y. (2019) · Translational Stroke Research · doi:10.1007/s12975-019-00709-8 · Cited by 60
Inflammation as common link to progressive neurological diseases
Dias-Carvalho, A., Sá, S. I., Carvalho, F., Fernandes, E., & Costa, V. M. (2024) · Archives of Toxicology · doi:10.1007/s00204-023-03628-8 · Cited by 60
“The weakening of the BBB after this inflammatory cascade allows the passage and neuronal uptake of many blood-cir-culating neurotoxins and reduces microvascular and cerebral blood flow (Bell et al. 2012).”
BackgroundMakedonov, I., Chen, J. J., Masellis, M., & MacIntosh, B. J. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.09.010 · Cited by 60
Dohi, K., Kraemer, B. C., Erickson, M. A., McMillan, P. J., Kováč, A., Flachbartova, Z., Hansen, K. M., Shah, G. N., Sheibani, N., Salameh, T. S., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0108034 · Cited by 60
“MMP-9 showed a biphasic increase, being elevated at 24 h and 7 days but not at 3 days; mHW reversed these increases (Figure 8, lower left panel).”
BackgroundInfluentialPericyte ALK5/TIMP3 Axis Contributes to Endothelial Morphogenesis in the Developing Brain
Dave, J. M., Mirabella, T., Weatherbee, S. D., & Greif, D. M. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.01.018 · Cited by 61
“PCs play a key role in inducing vascular stability (Benjamin et al. 1998), and PC coverage of ECs is critical for BBB regulation during development, maintenance and disease (Armulik et al. 2011, Armulik et al. 2010, Bell et al. 2012, Daneman et al. 2010).”
Background[Metabolic difference between visceral fat and subcutaneous abdominal fat].
Björntorp, P. A. (2000) · PubMed · Cited by 60
Uncovering Disease Mechanisms in a Novel Mouse Model Expressing Humanized APOEε4 and Trem2*R47H
Kotredes, K. P., Oblak, A., Pandey, R. S., Lin, P. B.-C., Garceau, D., Williams, H., Uyar, A., O’Rourke, R., O’Rourke, S., Ingraham, C., et al. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.735524 · Cited by 66
Fernandez, H. R., Varma, A., Flowers, S. A., & Rebeck, G. W. (2020) · Cancers · doi:10.3390/cancers12123842 · Cited by 65
“Cyclosporin A Inhibits pro-inflammatory cyclophilin A to reduce BBB breakdown Pre-clinical: reduced BBB leakage in APOE4 mice [57]”
BackgroundInfluentialThe APOEε3/ε4 Genotype Drives Distinct Gene Signatures in the Cortex of Young Mice
Foley, K. E., Hewes, A. A., Garceau, D. T., Kotredes, K. P., Carter, G. W., Sasner, M., & Howell, G. R. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.838436 · Cited by 62
“The frequency of LOAD increases from 20% in a non-carrier of APOEε4, to 47% when carrying one copy, and up to 91% when carrying two copies (Bell et al., 2012).”
BackgroundAnfray, A., Schaeffer, S., Hattori, Y., Santisteban, M. M., Casey, N., Wang, G., Strickland, M., Zhou, P., Holtzman, D. M., Anrather, J., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01757-6 · Cited by 53
“These alterations occur at an early age (2–3 months) and precede the BBB dysfunction 33,36 .”
Self-citationBlood-Brain Barrier: A Dual Life of MFSD2A?
Zhao, Z., & Zlokovic, B. V. (2014) · Neuron · doi:10.1016/j.neuron.2014.05.012 · Cited by 59
“…shown in other models of a chronic BBB breakdown including pericyte-deficient mice (Bell et al., 2010), apolipoprotein E4-express- ing mice (Bell et al., 2012), and/or after experimentally induced BBB breakdown in a mouse model of amyotrophic lateral sclerosis (ALS) (Winkler et al., 2014).”
BackgroundKatakura, Y., Totsuka, M., Imabayashi, E., Matsuda, H., & Hisatsune, T. (2017) · Nutrients · doi:10.3390/nu9111199 · Cited by 60
“Recently, Zlokovic and colleagues elegantly demonstrated the role of brain blood vessel pericytes in enabling brain microcapillaries to maintain brain blood flow, and suggested that pericyte degeneration contributes to the etiology of Alzheimer’s disease [36,37].”
BackgroundAPOE genotype affects the pre‐synaptic compartment of glutamatergic nerve terminals
Dumanis, S. B., DiBattista, A. M., Miessau, M., Moussa, C. E. H., & Rebeck, G. W. (2013) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2012.07908.x · Cited by 55
The Active Role of Pericytes During Neuroinflammation in the Adult Brain
Medina‐Flores, F., Hurtado‐Alvarado, G., Deli, M. A., & Gómez‐González, B. (2022) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-022-01208-5 · Cited by 63
A New Hypothesis for Alzheimer’s Disease: The Lipid Invasion Model
Rudge, J. D. (2022) · Journal of Alzheimer's Disease Reports · doi:10.3233/adr-210299 · Cited by 58
Remodeling of the Neurovascular Unit Following Cerebral Ischemia and Hemorrhage
Satō, Y., Falcone-Juengert, J., Tominaga, T., Su, H., & Liu, J. (2022) · Cells · doi:10.3390/cells11182823 · Cited by 60
“One likely reason is that ApoE directly modulates BBB integrity by inducing TJ formation or suppressing inflammation in the NVU [97,218].”
BackgroundInfluentialLiu, C., Yamazaki, Y., Heckman, M. G., Martens, Y. A., Jia, L., Yamazaki, A., Diehl, N. N., Zhao, J., Zhao, N., Deture, M. A., et al. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12104 · Cited by 59
Liu, S., Gao, J., Liu, K., & Zhang, H. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111560 · Cited by 59
Menaceur, C., Gosselet, F., Fénart, L., & Saint‐Pol, J. (2021) · Cells · doi:10.3390/cells11010133 · Cited by 64
Nelson, L., Gard, P., & Tabet, N. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-140024 · Cited by 59
“CypA activates gelatinases in cerebrovessel walls which leads to a disruption of the BBB by degrading tight junction proteins [118].”
BackgroundCerebral Vasoreactivity, Apolipoprotein E, and the Risk of Dementia
Wolters, F. J., de Bruijn, R. F. A. G., Albert Hofman, D., Koudstaal, P. J., & Ikram, M. A. (2015) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.115.306768 · Cited by 57
“Studies in mice have implicated APOEε4-mediated blood–brain barrier disruption in neurodegeneration, via a proinflammatory cyclophilin A—nuclear factor-κB—matrix-metalloproteinase 9 pathway in pericytes.(35) In humans, cognitively healthy APOEε4 carriers showed higher age-dependent blood–brain barrier breakdown than A…”
BackgroundBangen, K. J., Clark, A. L., Edmonds, E. C., Evangelista, N. D., Werhane, M. L., Thomas, K. R., Locano, L. E., Tran, M., Zlatar, Z. Z., Nation, D. A., et al. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00181 · Cited by 61
Johnson, L. A., Torres, E. R., Weber Boutros, S., Patel, E., Akinyeke, T., Alkayed, N. J., & Raber, J. (2019) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x17746186 · Cited by 56
“Interestingly, APOE genotype has recently been associated with BBB function in multiple studies, with E4 leading to increased BBB permeability, reductions in cerebral vascularization, thinner vessel walls and reduced CBF.(65,66) Importantly, vascular defects have been observed as early as two weeks of age in E4 mice,(…”
BackgroundResultInfluentialPathogenesis of Alzheimer's Disease: Role of Amyloid-beta and Hyperphosphorylated Tau Protein
Sajjad, R., Arif, R., Shah, A. A., Manzoor, I., & Mustafa, G. (2018) · Indian Journal of Pharmaceutical Sciences · doi:10.4172/pharmaceutical-sciences.1000397 · Cited by 57
van Buchem, M. A., Biessels, G. J., Rocca, H. B., de Craen, A. J. M., van der Flier, W. M., Ikram, M. A., Kappelle, L. J., Koudstaal, P. J., Mooijaart, S. P., Niessen, W. J., et al. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-141542 · Cited by 57
Ahmed, H., Wang, Y., Griffiths, W. J., Levey, A. I., Pikuleva, I. A., Liang, S. H., & Haider, A. (2024) · Brain · doi:10.1093/brain/awae028 · Cited by 61
Daulatzai, M. A. (2013) · Neurotoxicity Research · doi:10.1007/s12640-013-9407-2 · Cited by 56
“…dendritic spines, increased BBB susceptibility, regional CBF decline, cholinergic dysfunction, and reduced hippocampal activation (Berg et al. 1988; Schmechel et al. 1993; Lauderback et al. 2002; Gottlieb et al. 2004; Trivedi et al. 2006; Niu et al. 2009; Irimajiri et al. 2010; Bell et al. 2012).”
BackgroundVascular Contributions to Cognitive Impairment and Dementia
Madigan, J. B., Wilcock, D. M., & Hainsworth, A. H. (2016) · Stroke · doi:10.1161/strokeaha.116.012066 · Cited by 56
“This was dependent on MMP9 activity, induced via the proinflammatory cytokine cyclophilin-A.(25) None of these changes was evident in APOE2 or APOE3 TR mice.”
BackgroundInfluentialInhibition of 2-AG hydrolysis differentially regulates blood brain barrier permeability after injury
Piro, J. R., Suidan, G. L., Quan, J., Pi, Y., O'Neill, S., Ilardi, M. C., Pozdnyakov, N., Lanz, T. A., Xi, H. S., Bell, R. D., et al. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1166-9 · Cited by 56
“On day 3, each mouse was retro-orbitally injected with Alexa Fluor® 555-conjugated Cadaverine (Thermo A30677) at 500 μg/20 g body weight as previously described [21] or 200 μL of 25 mg/mL solution of fluorescein isothiocyanate (FITC)- conjugated dextran (70 kDa, Sigma Aldrich, St Louis, MO) in sterile saline.”
MethodSelf-citationZou, C., Mifflin, L., Hu, Z., Zhang, T., Shan, B., Wang, H., Xing, X., Zhu, H., Adiconis, X., Levin, J. Z., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108447 · Cited by 61
Apolipoprotein E as a β-amyloid-independent factor in Alzheimer’s disease
Wolf, A. B., Valla, J., Bu, G., Kim, J., LaDu, M., Reiman, E. M., & Caselli, R. J. (2013) · Alzheimer's Research & Therapy · doi:10.1186/alzrt204 · Cited by 55
“related protein 1 [86], suggesting that apoE4 may impair the BBB via a loss of function in comparison with the other isoforms.”
BackgroundKong, J., Yao, C., Dong, S., Wu, S., Xu, Y., Li, K., Liang, J., Shen, Q., Zhang, Q., Zhan, R., et al. (2021) · Advanced Science · doi:10.1002/advs.202002228 · Cited by 55
Cui, X., Chopp, M., Zacharek, A., Karasinska, J. M., Cui, Y., Ning, R., Zhang, Y., Wang, Y., & Chen, J. (2015) · Stroke · doi:10.1161/strokeaha.114.007145 · Cited by 57
“and astrocytes directly communicate with pericytes in addition to endothelial cells.(27) Pericyte deficiency in the central”
BackgroundShimokawa, H., & Satoh, K. (2015) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.115.305353 · Cited by 57
Laskowitz, D. T., Wang, H., Chen, T., Lubkin, D. T., Cantillana, V., Tu, T. M., Kernagis, D., Zhou, G., Macy, G., Kolls, B. J., et al. (2017) · Scientific Reports · doi:10.1038/srep46461 · Cited by 55
Reactive Astrocytes and Emerging Roles in Central Nervous System (CNS) Disorders
Liddelow, S. A., Olsen, M. L., & Sofroniew, M. V. (2024) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a041356 · Cited by 55
Nitric oxide‐mediated regulation of ‐amyloid clearance via alterations of MMP‐9/TIMP‐1
Ridnour, L. A., Dhanapal, S., Hoos, M., Wilson, J., Lee, J., Cheng, R. Y. S., Brueggemann, E. E., Hines, H. B., Wilcock, D. M., Vitek, M. P., et al. (2012) · Journal of Neurochemistry · doi:10.1111/jnc.12028 · Cited by 54
Abourehab, M. A. S., Khames, A., Genedy, S., Mostafa, S., Khaleel, M. A., Omar, M. M., & Sisi, A. M. E. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13040581 · Cited by 56
Ali, Z., Heverin, M., Olin, M., Acimovic, J., Lövgren-Sandblom, A., Shafaati, M., Båvner, A., Meiner, V., Leitersdorf, E., & Björkhem, I. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m034124 · Cited by 54
Lavrnja, I., Smiljanic, K., Savic, D., Mladenovic-Djordjevic, A., Tesovic, K., Kanazir, S., & Pekovic, S. (2017) · Scientific Reports · doi:10.1038/s41598-017-02638-8 · Cited by 54
“Additionally, it has been demonstrated to take part in antigen presentation 17 and maintenance of BBB integrity 18–20 , which is critical for the regulation of immune cell entry into the CNS.”
Li, Y., Wu, P., Bihl, J. C., & Shi, H. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200106154203 · Cited by 54
“Astrocytes also contribute to maintaining BBB function by inducing barrier properties and polarization of transporters [25-27].”
BackgroundAdult neurogenesis in Alzheimer's disease
Choi, S. H., & Tanzi, R. E. (2023) · Hippocampus · doi:10.1002/hipo.23504 · Cited by 54
“ApoE is involved in the lipid metabolism, Aβ clearance, and maintenance of the blood–brain barrier (BBB) integrity (Bell et al., 2012; Jiang et al., 2008; Mauch et al., 2001; Vance et al., 2000).”
BackgroundKisler, K., Lazić, D., Sweeney, M. D., Plunkett, S., Khatib, M. E., Vinogradov, S. A., Boas, D. A., Sakadžić, S., & Zloković, B. V. (2018) · Nature Protocols · doi:10.1038/nprot.2018.034 · Cited by 53
Rasmussen, K. L., Nordestgaard, B. G., Frikke‐Schmidt, R., & Nielsen, S. F. (2018) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2018.07.223 · Cited by 57
“For Alzheimer pathology driven by the immune system, infection, and inflammation, complement activation serves a central role in the innate immune system, and complement factors interact with glia cells, although details of the mechanisms are still unknown [9,13,48,53].”
BackgroundResultMolecular Insight into the Therapeutic Promise of TargetingAPOE4for Alzheimer’s Disease
Mamun, A. A., Uddin, M. S., Bashar, M. F. B., Zaman, S., Begum, Y., Bulbul, I. J., Islam, M. S., Sarwar, M. S., Mathew, B., Amran, M. S., et al. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/5086250 · Cited by 54
“Agedependent BBB breakdown as determined by the QAlb index along with raised CyA and active levels of MMP-9 were identified in CSF from cognitively regular APOE4 carriers [179].”
BackgroundInfluentialWojtas, A., Dammer, E. B., Guo, Q., Ping, L., Shantaraman, A., Duong, D. M., Yin, L., Fox, E. J., Seifar, F., Lee, E. B., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13821 · Cited by 57
Ehrlich, D., & Humpel, C. (2012) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2012.07.002 · Cited by 53
“Aβ) preceding neuronal degenerative changes, learning and memory impairment and neuroinflammatory response [18,19].”
Lin, F., Pei, L., Zhang, Q., Han, W., Jiang, S.-L., Lin, Y., Dong, B., Cui, L., & Li, M. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.26468 · Cited by 51
Dapsone protects brain microvascular integrity from high-fat diet induced LDL oxidation
Zhan, R., Zhao, M., Zhou, T., Chen, Y., Yu, W., Zhao, L., Zhang, T., Wang, H., Yang, H. M., Jin, Y., et al. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-0739-y · Cited by 53
Karreman, M. A., Bauer, A. T., Solecki, G. M., Berghoff, A. S., Mayer, C. D., Frey, K., Hebach, N. R., Feinauer, M. J., Schieber, N. L., Tehranian, C., et al. (2023) · Cancer Research · doi:10.1158/0008-5472.can-22-3964 · Cited by 51
Recombinant ADAMTS 13 Attenuates Brain Injury After Intracerebral Hemorrhage
Cai, P., Luo, H., Xu, H., Zhu, X., Xu, W., Dai, Y., Xiao, J., Cao, Y., Zhao, Y., Zhao, B., et al. (2015) · Stroke · doi:10.1161/strokeaha.115.009526 · Cited by 51
DNA damage response in peripheral nervous system: Coping with cancer therapy-induced DNA lesions
Englander, E. W. (2013) · DNA repair · doi:10.1016/j.dnarep.2013.04.020 · Cited by 52
“Ample evidence that links breaching of BBB with brain pathology, underscores the importance of BBB in maintaining CNS homeostasis and function [1, 2].”
BackgroundImmunoregulation at the gliovascular unit in the healthy brain: A focus on Connexin 43
Boulay, A.-C., Cisternino, S., & Cohen‐Salmon, M. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.11.017 · Cited by 51
Salameh, T. S., Rhea, E. M., Banks, W. A., & Hanson, A. J. (2016) · Experimental Biology and Medicine · doi:10.1177/1535370216660770 · Cited by 51
“Furthermore, APOE4 knock-in mice had higher levels of BBB breakdown in response to injury, via upregulation of the proinflammatory cyclophilin A pathway in pericytes.(12) The role that APOE plays in transport and clearance of molecules also depends on the APOE isoform, and these transport differences may be related to…”
BackgroundYang, X., Chen, S., Shao, Z., Li, Y., Wu, H., Li, X., Mao, L., Zhou, Z., Bai, L., Mei, X., et al. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00142 · Cited by 52
Butiaeva, L. I., Slutzki, T., Swick, H. E., Bourguignon, C., Robins, S. C., Liu, X., Storch, K.-F., & Kokoeva, M. V. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.05.017 · Cited by 49
Cognitive Dysfunction after Heart Disease: A Manifestation of the Heart‐Brain Axis
Xu, C., Tao, X., Ma, X., Zhao, R., & Cao, Z. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/4899688 · Cited by 53
“In addition, pericytes are reportedly involved in regulating BBB function and are highly likely to cause destructive inflammation [85, 90].”
BackgroundA phase 2 study of thalidomide for the treatment of radiation-induced blood-brain barrier injury
Cheng, J., Jiang, J., He, B., Lin, W., Li, Y., Duan, J., Li, H., Huang, X., Cai, J., Xie, J., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.abm6543 · Cited by 54
Tipping points in neurodegeneration
Simons, M., Levin, J., & Dichgans, M. (2023) · Neuron · doi:10.1016/j.neuron.2023.05.031 · Cited by 52
The Alzheimer's disease risk factor CD2AP maintains blood–brain barrier integrity
Cochran, J. N., Rush, T., Buckingham, S. C., & Roberson, E. D. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv371 · Cited by 52
Cyclophilin A in Cardiovascular Homeostasis and Diseases
Satoh, K. (2014) · The Tohoku Journal of Experimental Medicine · doi:10.1620/tjem.235.1 · Cited by 50
“The atheroprotection observed in these animals was due to the decreased levels of EC inflammation mediated by the absence of CyPA (Bell et al. 2012).”
BackgroundPeptidyl-prolyl isomerases: a full cast of critical actors in cardiovascular diseases
Perrucci, G. L., Gowran, A., Zanobini, M., Capogrossi, M. C., Pompilio, G., & Nigro, P. (2015) · Cardiovascular Research · doi:10.1093/cvr/cvv096 · Cited by 50
Wu, Y., Pang, J., Peng, J., Cao, F., Vitek, M. P., Li, F., Jiang, Y. Q., & Sun, X. (2016) · Neuroscience Letters · doi:10.1016/j.neulet.2016.05.058 · Cited by 50
RetractedEngstrom, A. K., Snyder, J. M., Maeda, N., & Xia, Z. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0155-2 · Cited by 51
T Cells—Protective or Pathogenic in Alzheimer’s Disease?
McManus, R. M., Mills, K. H. G., & Lynch, M. A. (2015) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-015-9612-2 · Cited by 54
“Whereas mice expressing the human APOE2 or APOE3 had an intact BBB, mice expressing APOE4 exhibited significant disruption of the barrier as demonstrated by enhanced leakage of IgG, thrombin and fibrin, coupled with increased activity of MMP-9 and decreased claudin-5, occludin and ZO-1 (Bell et al. 2012).”
BackgroundInfluentialDhanesha, N., Jain, M. K., Tripathi, A. K., Doddapattar, P., Chorawala, M. R., Bathla, G., Nayak, M. K., Ghatge, M., Lentz, S. R., Kon, S., et al. (2020) · Circulation Research · doi:10.1161/circresaha.120.316659 · Cited by 49
Nutritional metabolism and cerebral bioenergetics in Alzheimer's disease and related dementias
Yassine, H. N., Self, W. K., Kerman, B. E., Santoni, G., Shanmugam, N. K. N., Abdullah, L. I., Golden, L. R., Fonteh, A. N., Harrington, M. G., Gräff, J., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12845 · Cited by 52
Cao, Y., Li, Z., Li, H., Ni, C., Li, L., Yang, N., Shi, C., Zhong, Y., Cui, D., & Guo, X. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.09.004 · Cited by 49
“Brain capillaries were isolated using dextran gradient centrifugation as previously described [18].”
Lee, E., Yoon, J., Choi, J., Andika, F. R., Lee, T., & Jeong, Y. (2017) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x17736963 · Cited by 49
Key Peptides and Proteins in Alzheimer’s Disease
Penke, B., Bogár, F., Paragi, G., Gera, J., & Fülöp, L. (2019) · Current Protein and Peptide Science · doi:10.2174/1389203720666190103123434 · Cited by 51
Discovery of novel amide tripeptides as pancreatic lipase inhibitors by virtual screening
Stefanucci, A., Dimmito, M. P., Zengin, G., Luisi, G., Mirzaie, S., Novellino, E., & Mollica, A. (2019) · New Journal of Chemistry · doi:10.1039/c8nj05884a · Cited by 49
Pericytes Across the Lifetime in the Central Nervous System
Bennett, H. C., & Kim, Y. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.627291 · Cited by 49
Yue, Q., Leng, X., Xie, N., Zhang, Z., Yang, D., & Hoi, M. P. M. (2024) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.70079 · Cited by 48
The potential applications of Apolipoprotein E in personalized medicine
Villeneuve, S., Brisson, D., Marchant, N. L., & Gaudet, D. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00154 · Cited by 50
“While several routes exist for the clearance of Aβ, clearance directly into the blood seems to be the predominant pathway in the human brain (Bell and Zlokovic, 2009; Bell et al., 2012).”
BackgroundDuarte, A. I., Santos, M. S., Oliveira, C. R., & Moreira, P. I. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.01.044 · Cited by 49
“The choroid plexus vs. BBB endothelium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 1.3.2.”
InfluentialQin, H., Jiang, Y., Zhang, J., Deng, C., & Zhong, Z. (2019) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.9b00691 · Cited by 49
Schreiber, S., Wilisch-Neumann, A., Schreiber, F., Assmann, A., Scheumann, V., Perosa, V., Jandke, S., Mawrin, C., Carare, R. O., & Werring, D. J. (2019) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12576 · Cited by 50
Zhang, L., Wang, H., Abel, G. M., Storm, D. R., & Xia, Z. (2019) · Toxicological Sciences · doi:10.1093/toxsci/kfz218 · Cited by 48
“is possible that ApoE4 may cause leakage on the blood-brain barrier (Bell et al., 2012) and lead to higher degree of Cd accumulation in the ApoE4 brain.”
BackgroundZhang, Z., Na, H., Gan, Q., Tao, Q., Alekseyev, Y., Hu, J., Yan, Z., Yang, J. B., Tian, H., Zhu, S., et al. (2021) · Aging Cell · doi:10.1111/acel.13501 · Cited by 45
Stroke and Vascular Cognitive Impairment: The Role of Intestinal Microbiota Metabolite TMAO
Tu, R., & Xia, J. (2024) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527322666230203140805 · Cited by 47
Early- and Late-Onset Alzheimer’s Disease: Two Sides of the Same Coin?
Valdez-Gaxiola, C. A., Rosales-Leycegui, F., Gaxiola-Rubio, A., Moreno-Ortíz, J. M., & Figuera, L. E. (2024) · Diseases · doi:10.3390/diseases12060110 · Cited by 55
“Proposed mechanisms underlying this effect include the activation of cyclophilin A, leading to elevated levels of MMP9 and pericyte injury, as well as disruption of the capillary basement membrane [155].”
BackgroundMuradashvili, N., Tyagi, R., Metreveli, N. S., Tyagi, S. C., & Lominadze, D. G. (2014) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2014.102 · Cited by 47
Satoh, K., Godo, S., Saito, H., Enkhjargal, B., & Shimokawa, H. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2013.12.022 · Cited by 47
“The atheroprotection observed in ApoE−/−CyPA−/−micewas due to the decreased levels of inflammation mediated by the absence of CyPA [62].”
BackgroundThe Vasculome of the Mouse Brain
Guo, S., Zhou, Y., Xing, C., Lok, J. M., Som, A. T., Ning, M., Ji, X., & Lo, E. H. (2012) · PLoS ONE · doi:10.1371/journal.pone.0052665 · Cited by 47
“Signals from astrocytes and pericytes provide important regulatory mechanisms for the blood-brain barrier [6,7,8].”
BackgroundEvaluation of dietary and lifestyle changes as modifiers of S100β levels in Alzheimer’s disease
D'Cunha, N. M., McKune, A. J., Panagiotakos, D. B., Georgousopoulou, E. N., Thomas, J., Mellor, D. D., & Naumovski, N. (2017) · Nutritional Neuroscience · doi:10.1080/1028415x.2017.1349032 · Cited by 47
“APOE4 genotype has been linked to BBB dysfunction, and the presence of APOE4 may exacerbate the deleterious effects of high S100β levels (106).”
BackgroundContribution of astrocytes to metabolic dysfunction in the Alzheimer’s disease brain
Zulfiqar, S., Garg, P., & Nieweg, K. (2019) · Biological Chemistry · doi:10.1515/hsz-2019-0140 · Cited by 46
ApoE and cerebral insulin: Trafficking, receptors, and resistance
Rhea, E. M., Raber, J., & Banks, W. A. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104755 · Cited by 50
Rohn, T. T., Catlin, L. W., Coonse, K., & Habig, J. W. (2012) · Brain Research · doi:10.1016/j.brainres.2012.08.003 · Cited by 44
Watson, A. N., Berthiaume, A., Faino, A., McDowell, K. P., Bhat, N. R., Hartmann, D. A., & Shih, A. Y. (2020) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x19900543 · Cited by 44
“This extent of pericyte loss was associated with activation of CypA-MMP9 in pericytes, which is a trigger for BBB breakdown.(36) Another study reported 25% decrease in NG2-positive pericyte somata in AD patients.”
BackgroundRod‐Shaped Polymeric Nanoparticles Intervene Neutrophils for Efficient Ischemic Stroke Therapy
Song, Z., Fang, J., Wang, Z., Xiao, R., Guo, X., & Zhou, S. (2023) · Advanced Functional Materials · doi:10.1002/adfm.202212326 · Cited by 46
Minocycline Reduces Spontaneous Hemorrhage in Mouse Models of Cerebral Amyloid Angiopathy
Yan, P., Zhu, A., Liao, F., Xiao, Q.-L., Kraft, A. W., Gonzales, E., Perez, R., Greenberg, S., Holtzman, D., & Lee, J.-M. (2015) · Stroke · doi:10.1161/strokeaha.115.008582 · Cited by 35
“proteins (ZO-1, occluding, and claudin 5), leading to compromise of the BBB.(30) To determine whether minocycline”
BackgroundInfluentialSelf-citationEhrenreich, H. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00181 · Cited by 46
“Along the same lines, we investigated APOE4 carriers since the APOE4 haplotype has been associated with a permeable BBB (32, 33).”
BackgroundAstrocytes Mediate Protective Actions of Estrogenic Compounds after Traumatic Brain Injury
Martín-Jiménez, C., Gaitán-Vaca, D. M., Mazo, N. A., Echeverrı́a, V., Ashraf, G. M., González, J., Sahebkar, A., García‐Segura, L. M., & Barreto, G. E. (2018) · Neuroendocrinology · doi:10.1159/000495078 · Cited by 45
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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