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, APOE4 secreted from astrocytes binds LRP1 on pericytes and induces proinflammatory CypA expression, activating NF-kB and MMP9.
“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]
The paper reports increased pericyte CypA expression and NF-κB–MMP9 activation in APOE4 mice, but it gives the opposite account of the claimed receptor interaction. In the supplied passage labelled Abstract, APOE4–LRP1 binding is described as barely detectable; APOE4 fails to suppress CypA through LRP1, rather than binding LRP1 to induce it. No page number is provided. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredReduced expression of tight junction proteins is found in AD mouse model with increased MMP9 activities.
“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]
The paper reports increased activated MMP9 in Apoe−/− and TR-APOE4 mice and reduced tight-junction proteins in their brain microvessels (passages [1]–[2], section labelled Abstract; no page given). It describes these as APOE-related mouse lines, not specifically as AD mouse models, so the claim's model designation is not established by our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAstrocytes secrete apolipoprotein E (APOE) to signal pericytes via low-density lipoprotein receptor-related protein-1 (LRP1), which suppresses activation of the 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.
“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]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredIn transgenic mice expressing human APOE isoforms, astrocyte-secreted APOE2 and APOE3 bind to LRP1 on pericytes in vivo, which inhibits the proinflammatory CypA-MMP-9 pathway, preventing degradation of blood-brain barrier tight junction and basement membrane proteins.
“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]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredAPOE exerts toxic effects on the cerebrovascular system and neurons and influences Aβ clearance, amyloid deposition, and tau-related neurodegeneration in an allele-dependent manner APOE4 > APOE3 > APOE2.
“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]
The indexed paper (Abstract; page unavailable) reports BBB breakdown and microvascular injury in APOE4 mice, but not in APOE2 or APOE3 mice, supporting the cerebrovascular part attributed to citation 694. It does not establish the stated APOE4 > APOE3 > APOE2 ordering for cerebrovascular harm; it describes APOE2 and APOE3 alike as maintaining BBB integrity. The citing sentence assigns its neuronal, amyloid, and tau claims to other citations. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Apoe-/- mice also develop secondary neurodegenerative changes after BBB breakdown in the absence of Aβ pathology.
“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]
The paper’s main text (indexed as Abstract; page unavailable) reports that BBB defects appeared in Apoe−/− mice before neuronal and synaptic changes, and that later changes improved when BBB integrity was restored. Our copy does not establish that these mice lacked Aβ pathology, so that qualifier is unsupported. (LLM, conf=0.84)
Experimental — accuracy not yet measuredNeuroinflammation is another key hallmark in AD brain.
“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]
The paper’s Abstract reports activation of a proinflammatory pathway in APOE4-expressing mice and links APOE4 to Alzheimer’s disease. It does not establish that neuroinflammation is a key hallmark of the Alzheimer’s disease brain; its stated finding concerns a pathway in a mouse model. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe disease spectrum comprising Alzheimer disease, vascular dementia, and cerebrovascular disease is 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.
“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]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredApoE 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.
“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]
The paper reports in its main text (page unavailable) that APOE2 and APOE3 maintain blood–brain barrier integrity in mice, whereas APOE4 promotes disruption. Our copy does not establish the sentence’s additional claims about cerebral cholesterol metabolism, brain amyloid metabolism, or transport of lipids to neurons; searches for cholesterol, lipid transport, and amyloid clearance did not find supporting discussion. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe similar findings 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 β-amyloid clearance.
“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]
The paper reports that Apoe-deficient mice develop blood–brain barrier breakdown, microvascular defects and later neuronal changes (Abstract; page not provided). This supports a role for apoE in cerebrovascular integrity, but the cited passages do not establish that rare low-apoE variants impair local lipid transport or β-amyloid clearance. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBrain apoE plays a major role in brain amyloid metabolism, in blood-brain barrier integrity, and in supplying cholesterol and phospholipids to neuronal cells.
“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 <i>APOE</i> and dementia – resequencing and genotyping in 105,597 individuals (2020) · cites this paper as [12]
The paper’s main text (indexed under Abstract; no page given) reports that APOE2 and APOE3 maintain blood–brain barrier integrity in mice, while APOE4 promotes its disruption. The passages found do not establish the other attributed roles—brain amyloid metabolism or supplying cholesterol and phospholipids to neuronal cells (searched those terms and amyloid-beta clearance). (LLM, conf=0.87)
Experimental — accuracy not yet measuredPericyte inflammation leads to neuronal uptake of neurotoxic proteins from the blood, microvascular and cerebral blood flow reductions, and subsequently impaired clearance of amyloid-b.
“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]
The paper reports that activation of a proinflammatory pathway in pericytes of APOE4-expressing and Apoe-deficient mice leads to neuronal uptake of blood-derived neurotoxic proteins and reductions in microvasculature and cerebral blood flow (opening summary, page unavailable). It does not say that these changes subsequently impair amyloid-β clearance; clearance appears in the titles of works in its References, not as a finding establishing that sequence. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPeripheral APOE seems to influence the brain partly by impacting the BBB.
“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]
The paper’s Abstract reports that APOE affects BBB integrity in mice and that BBB breakdown permits blood-derived proteins to enter the brain. But the mechanism it examines involves astrocyte-secreted APOE; our copy does not establish that peripheral APOE has this effect. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCompared 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 allele.
“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]
The paper reports a leaky BBB in APOE4-expressing and Apoe knockout mice, compared with mice expressing APOE2 or APOE3 (Abstract; no page given). It also mentions neurovascular dysfunction in normal human APOE4 carriers, but does not establish BBB leakage in cognitively unimpaired or mildly impaired carriers. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAPOE4 alters blood-brain barrier integrity, influencing metabolite exchange between the periphery and CNS, including reduced brain glucose and lipid transport.
“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]
The paper reports that APOE4-expressing mice have a leaky blood–brain barrier and increased entry of blood-derived proteins into the brain (Abstract; page not provided). This supports altered barrier integrity and exchange across it, but the paper does not report reduced brain glucose or lipid transport. (LLM, conf=0.87)
Experimental — accuracy not yet measuredTransgenic expression of human APOE4 in mice leads to uncontrolled expression of proinflammatory cyclophilin A (CypA) in pericytes, inducing activation of NF-kB and matrix metalloproteinase 9 (MMP9), which in turn results in BBB breakdown.
“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]
Transgenic mice lacking Apoe develop an early BBB breakdown.
“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]
LRP1 on pericytes regulates cerebrovascular integrity in an APOE-dependent fashion.
“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]
APOE4 has a low affinity for LRP1, which activates the CypA-MMP-9 pathway, causing blood-brain barrier breakdown.
“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]
Transgenic mice expressing human APOE4 gene, but not APOE3 and APOE2, develop an early BBB breakdown, cerebral microhemorrhages, and loss of endothelial GLUT1 expression that is followed by secondary neurodegenerative changes.
“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]
Inhibition of the CypA-MMP-9 blood-brain barrier degrading pathway by cyclosporine, a CypA inhibitor, restored blood-brain barrier integrity and reversed secondary neurodegenerative changes in transgenic humanized APOE4 mice.
“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]
These vascular changes precede neuronal dysfunction and neurodegeneration, but can be reversed by sealing the BBB.
“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]
Recent evidence indicates that apoE4 expression compromises the blood-brain barrier, as does apoE deficiency.
“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]
Lack of murine Apoe protein and targeted replacement of murine Apoe with human apoE4 lead to blood-brain barrier breakdown by activating a proinflammatory cyclophilin A-nuclear factor kB-matrix metalloproteinase-9 pathway in pericytes.
“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]
Vascular defects have been detected in human apoE4-targeted replacement mice, but not apoE3-TR mice, at 2 weeks of age.
“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
Inflammatory factors including IL-1, IL-6, GM-CSF, IL-12, IL-23, and TNF-α are all upregulated under Alzheimer's disease conditions.
“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]
The paper’s main text (page unavailable) describes a proinflammatory CypA–NF-κB–MMP9 pathway in APOE4 and Apoe-deficient mice, but does not report that the listed cytokines are upregulated under Alzheimer’s disease conditions. Searches for IL-1, IL-6, GM-CSF, IL-12, IL-23, TNF-α, and their broader terms found no passage addressing that claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredInflammation is a prominent, long-observed but poorly understood component of SVD; inflammatory cell infiltrates were noted pathologically over 110 years ago in penetrating arterioles and perivascular tissue in SVD and consistently since, and plasma inflammatory markers are elevated in lacunar stroke and genetically associated with WMH progression and lacunar infarcts.
“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]
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.
“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
ApoE4, a major genetic risk factor for Alzheimer's disease, causes blood-brain barrier disruption through a proinflammatory pathway involving cyclophilin A in pericytes.
“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
APOE4 triggers inflammatory cascades, leading to neurovascular dysfunction, BBB degeneration, penetration of toxic proteins from blood into brain, and reduced length of small blood vessels.
“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]
ApoE4 may mediate neuropathological effects by directly modulating blood-brain barrier integrity; ApoE4 does not efficiently engage LRP1 on pericytes, leading to a proinflammatory cascade and BBB breakdown.
“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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Reduced levels of human apoE4 protein in an animal model of cognitive impairment
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Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
Liu, C.-C., Kanekiyo, T., Xu, H., & Bu, G. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.263 · Cited by 3,459 · see citing works
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
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“Exposure to serum proteins can then contribute to neurodegeneration (Bell et al., 2012; Zlokovic, 2013).”
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Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders
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Self-citationDevelopment, maintenance and disruption of the blood-brain barrier
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Blood-Brain Barrier: From Physiology to Disease and Back
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Blood-brain barrier breakdown in the aging human hippocampus
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“PDGFRβ is an established marker of the BBBassociated pericytes (Armulik et al., 2010; Bell et al., 2010, 2012; Winkler et al., 2011 ) that play a key role in maintaining the BBB integrity (Zlokovic, 2008, 2011; Iadecola, 2013; Daneman et al., 2010; Armulik et al., 2010; Bell et al., 2010, 2012;…”
InfluentialSelf-citationThe Cellular Phase of Alzheimer’s Disease
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The Pathobiology of Vascular Dementia
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A blood–brain barrier overview on structure, function, impairment, and biomarkers of integrity
Kadry, H., Noorani, B., & Cucullo, L. (2020) · Fluids and Barriers of the CNS · doi:10.1186/s12987-020-00230-3 · Cited by 1,853 · see citing works
“Studies in APOE4 transgenic mice suggested that vascular changes may occur early and proceeded by the neuronal behavioral changes [210].”
BackgroundClearance systems in the brain—implications for Alzheimer disease
Tarasoff-Conway, J. M., Carare, R. O., Osorio, R. S., Glodzik, L., Butler, T., Fieremans, E., Axel, L., Rusinek, H., Nicholson, C., Zlokovic, B. V., et al. (2015) · Nature Reviews Neurology · doi:10.1038/nrneurol.2015.119 · Cited by 1,678 · see citing works
Establishment and Dysfunction of the Blood-Brain Barrier
Zhao, Z., Nelson, A. R., Betsholtz, C., & Zlokovic, B. V. (2015) · Cell · doi:10.1016/j.cell.2015.10.067 · Cited by 1,670 · see citing works
Self-citationMechanisms of sporadic cerebral small vessel disease: insights from neuroimaging
Wardlaw, J. M., Smith, C., & Dichgans, M. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(13)70060-7 · Cited by 1,657 · see citing works
Role of neuroinflammation in neurodegeneration development
Zhang, W., Xiao, D., Mao, Q., & Xia, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01486-5 · Cited by 1,668 · see citing works
“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) APOE4 even induces cognitive decline independent of Aβ or tau pathol…”
BackgroundApolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C., & Bu, G. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0228-7 · Cited by 1,425 · see citing works
Reactive Gliosis and the Multicellular Response to CNS Damage and Disease
Burda, J. E., & Sofroniew, M. V. (2014) · Neuron · doi:10.1016/j.neuron.2013.12.034 · Cited by 1,431 · see citing works
APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline
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Self-citationCerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease
Kisler, K., Nelson, A. R., Montagne, A., & Zlokovic, B. V. (2017) · Nature Reviews Neuroscience · doi:10.1038/nrn.2017.48 · Cited by 1,243 · see citing works
From blood–brain barrier to blood–brain interface: new opportunities for CNS drug delivery
Banks, W. A. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.21 · Cited by 1,204 · see citing works
“1α,25-dihydroxyvitam D3 enhances cerebral clearance of human amyloid-β peptide(1-40) from mouse brain across the blood–brain barrier.”
BackgroundAstrocyte barriers to neurotoxic inflammation
Sofroniew, M. V. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3898 · Cited by 1,202 · see citing works
Pericytes of the neurovascular unit: key functions and signaling pathways
Sweeney, M. D., Ayyadurai, S., & Zlokovic, B. V. (2016) · Nature Neuroscience · doi:10.1038/nn.4288 · Cited by 1,125 · see citing works
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994 · see citing works
“flammatory 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].”
BackgroundThe role of brain vasculature in neurodegenerative disorders
Sweeney, M. D., Kisler, K., Montagne, A., Toga, A. W., & Zlokovic, B. V. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0234-x · Cited by 998 · see citing works
Mfsd2a is critical for the formation and function of the blood-brain barrier
Ben-Zvi, A., Lacoste, B., Kur, E., Andreone, B. J., Mayshar, Y., Yan, H., & Gu, C. (2014) · Nature · doi:10.1038/nature13324 · Cited by 1,037 · see citing works
APOE and Alzheimer’s disease: Advances in genetics, pathophysiology, and therapeutic approaches
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Blood-brain barrier dysfunction and recovery after ischemic stroke
Jiang, X., Andjelkovic, A. V., Zhu, L., Yang, T., Bennett, M. V. L., Chen, J., Keep, R. F., & Shi, Y. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.10.001 · Cited by 946 · see citing works
Apolipoprotein E: Structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases
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Matrix metalloproteinases in the brain and blood–brain barrier: Versatile breakers and makers
Rempe, R. G., Hartz, A. M. S., & Bauer, B. (2016) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x16655551 · Cited by 784 · see citing works
“A further development of this method is in vivo zymography,(114) where substrates are used in a live animal to detect MMP activity in vivo.(115) MMPs in central nervous system disease”
MethodThe blood-brain barrier in Alzheimer’s disease
Zenaro, E., Piacentino, G., & Constantin, G. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.07.007 · Cited by 767 · see citing works
“…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).”
The blood–brain barrier in health and disease: Important unanswered questions
Profaci, C. P., Munji, R. N., Pulido, R. S., & Daneman, R. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20190062 · Cited by 777 · see citing works
“creased TJ proteins and MMP9 elevation along with pericyte degeneration in APOE4 carriers (Bell et al., 2012; Halliday et al., 2016; Nishitsuji et al., 2011).”
BackgroundAstrocyte roles in traumatic brain injury
Burda, J. E., Bernstein, A. M., & Sofroniew, M. V. (2015) · Experimental Neurology · doi:10.1016/j.expneurol.2015.03.020 · Cited by 758 · see citing works
“In addition, apolipoprotein E (APOE) secretion by astrocytes suppresses a cyclophilin A-NFκB-matrix metaloproteinase-9 pathway in pericytes that increases blood brain barrier permeability and is pro-inflammatory (Bell et al., 2012).”
BackgroundInfluentialThe blood–brain barrier in systemic infection and inflammation
Galea, I. (2021) · Cellular and Molecular Immunology · doi:10.1038/s41423-021-00757-x · Cited by 762 · see citing works
“One mechanism underlying this phenomenon is thought to be a loss of constitutive suppression of the cyclophilin A–nuclear factorκB–matrix-metalloproteinase-9 pathway within pericytes that leads to MMP9-mediated degradation of capillary basement membrane and tight-junction proteins, and hence BBB leakage [131].”
BackgroundThe blood-brain barrier in aging and neurodegeneration
Knox, E. G., Aburto, M. R., Clarke, G., Cryan, J. F., & O’Driscoll, C. M. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01511-z · Cited by 738 · see citing works
“Other potential therapeutics include specific inhibitors and genetic manipulation of cyclophilin A (CypA) which can ameliorate the vascular and neuronal dysfunction found in AD model mice through inhibition of the CypA — nuclear factor kappa B (NF-κB) — matrix metalloproteinases-9 pathway [137, 138].”
BackgroundAlzheimer’s disease: A matter of blood–brain barrier dysfunction?
Montagne, A., Zhao, Z., & Zlokovic, B. V. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20171406 · Cited by 672 · see citing works
GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration
Winkler, E. A., Nishida, Y., Sagare, A. P., Rege, S. V., Bell, R. D., Perlmutter, D., Sengillo, J. D., Hillman, S., Kong, P., Nelson, A. R., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.3966 · Cited by 689 · see citing works
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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 · see citing works
Age, APOE and sex: triad of risk of Alzheimer’s disease.
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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-citationRETRACTED 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 · see citing works
Self-citationRetractedApoE and Aβ in Alzheimer’s Disease: Accidental Encounters or Partners?
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The 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 · see citing works
“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 · see citing works
“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 · see citing works
Vascular contributions to cognitive impairment and dementia including Alzheimer's disease
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“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 · see citing works
Disruption of astrocyte–vascular coupling and the blood–brain barrier by invading glioma cells
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Glial influence on the blood brain barrier
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“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 546 · see citing works
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 · see citing works
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 · see citing works
Cyclophilin A: a key player for human disease
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“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 465 · see citing works
“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 431 · see citing works
Age-associated Physiological and Pathological Changes at the Blood-Brain Barrier: A Review
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“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 · see citing works
Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance
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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 · see citing works
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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 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 · see citing works
“…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 382 · see citing works
Self-citationApolipoprotein E in lipoprotein metabolism, health and cardiovascular disease
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Seven sirtuins for seven deadly diseases ofaging
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“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 · see citing works
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 · see citing works
Blood–spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis
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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 · see citing works
Self-citationRetractedApoE 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 · see citing works
“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-citation<i>APOE</i> 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 · see citing works
“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 356 · see citing works
“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 · see citing works
Self-citationApoE attenuates unresolvable inflammation by complex formation with activated C1q
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Focused ultrasound-mediated drug delivery through the blood–brain barrier
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“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 · see citing works
“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 · see citing works
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 326 · see citing works
“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 307 · see citing works
“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 · see citing works
“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].”
BackgroundResultHammer, 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 · see citing works
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 296 · see citing works
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 300 · see citing works
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 · see citing works
“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-citationShinohara, M., Tachibana, M., Kanekiyo, T., & Bu, G. (2017) · Journal of Lipid Research · doi:10.1194/jlr.r075796 · Cited by 297 · see citing works
“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 293 · see citing works
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 · see citing works
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 283 · see citing works
“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 282 · see citing works
Kanekiyo, T., & Bu, G. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00093 · Cited by 281 · see citing works
“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 · see citing works
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 275 · see citing works
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 · see citing works
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 275 · see citing works
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 271 · see citing works
“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 265 · see citing works
“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 263 · see citing works
“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 261 · see citing works
“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 · see citing works
“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 265 · see citing works
“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
- 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
- Health Sciences › Medicine › Physiology › 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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