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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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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
“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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In the citing paper
“Apoe -/ -mice also develop secondary neurodegenerative changes after BBB breakdown in the absence of A 𝛃 pathology (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Neuroinflammation is another key hallmark in AD brain.[ 23 ]”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [23]
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
“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]
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
“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.
In the citing paper
“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]
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
“Pericyte inflammation leads to neuronal uptake of neurotoxic proteins from the blood, and microvascular and cerebral blood flow reductions, which altogether subsequently lead to impaired clearance of amyloid-b [86,87].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [87]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“peripheral APOE seems to influence the brain partly by impacting the BBB.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [183]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“When compared with wild-type mice, both Apoe knockout mice and mice expressing APOE4 have a leaky BBB, a phenomenon also reported in cognitively unimpaired and mildly impaired individuals who carry an APOEε4 allele183–185.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [183]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“APOE4 alters the integrity of the blood brain barrier (BBB) influencing metabolite exchange between the periphery and the central nervous system (CNS) including reduced brain glucose and lipid transport [17][18][19] .”
From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [17]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“This hypothesis was the initial driver that defined a plethora of surprising functions of LDL receptor-related proteins (LRPs) in the central and peripheral nervous system (Bal et al., 2013; Beffert et al., 2005; Bell et al., 2012; Choi et al., 2013; Kim et al., 2008; Lane-Donovan and Herz, 2017; Liu et al., 2013; Liu et al., 2007; Liu et al., 2011; May et al., 2004; Nakajima et al., 2013; Pohl”
From Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease (2018) · cites this paper as Bell et al., 2012
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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
The cited source says what the claim attributes to it.
In the citing paper
“Transgenic expression of human APOE4 in the mice led to uncontrolled expression of proinflammatory cyclophilin A (CypA) in pericytes, inducing the activation of NF-kB and matrix metalloproteinase 9 (MMP9), which in turn results in BBB breakdown.183”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [183]
The cited source says what the claim attributes to it.
In the citing paper
“Transgenic mice lacking Apoe also develop an early BBB breakdown (60, 99, 147, 187, 226, 233, 406, 426, 437, 554), indicating that APOE is essential for maintaining BBB integrity.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
The cited source says what the claim attributes to it.
In the citing paper
“Additionally, LRP1 on pericytes regulates cerebrovascular integrity in an APOE-dependent fashion (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
The cited source says what the claim attributes to it.
In the citing paper
“On the other hand, APOE4 has a low affinity for LRP1, which activates CypA-MMP-9 pathway causing BBB breakdown (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
The cited source says what the claim attributes to it.
In the citing paper
“Transgenic mice expressing human APOE4 gene, but not APOE3 and APOE 2, develop an early BBB breakdown (60, 437), cerebral microhemorrhages (85), and loss of endothelial GLUT1 expression (9) that is followed by secondary neurodegenerative changes (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
The cited source says what the claim attributes to it.
In the citing paper
“Inhibition of CypA-MMP-9 BBB degrading pathway by cyclosporine, a CypA inhibitor, restored BBB integrity and reversed secondary neurodegenerative changes in transgenic humanized APOE4 mice (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
The cited source says what the claim attributes to it.
In the citing paper
“These vascular changes precede neuronal dysfunction and neurodegeneration, but can be reversed by sealing the BBB (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
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In the citing paper
“However, recent evidence indicates that apoE4 expression compromises the blood-brain barrier (as does apoE deficiency).40”
From Effects of the Absence of Apolipoprotein E on Lipoproteins, Neurocognitive Function, and Retinal Function (2014) · cites this paper as [40]
The cited source says what the claim attributes to it.
In the citing paper
“Both the level of apoE and apoE isoform plays a role: lack of murine Apoe protein as well as targeted replacement of murine Apoe with human apoE4, leads to blood-brain barrier breakdown by activating a proinflammatory cyclophilin A-nuclear factor kB-matrix metalloproteinase-9 pathway in pericytes [87].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [87]
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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
“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]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
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
“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
“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
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“Indeed, pericytes have already been shown to respond to the astrocytic release of apoE by stopping the production of MMP-9, which would lead to BBB disruption if unregulated [15].”
BackgroundBouleti, C., Mathivet, T., Coqueran, B., Serfaty, J., Lesage, M., Berland, E., Ardidie‐Robouant, C., Kauffenstein, G., Henrion, D., Lapergue, B., et al. (2013) · European Heart Journal · doi:10.1093/eurheartj/eht153 · Cited by 92
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“Activation of this pathway results in microvascular and CBF reduction, being independent of the Aβ deposition [110,111].”
BackgroundZerche, M., Weißenborn, K., Ott, C., Dere, E., Asif, A. R., Worthmann, H., Hassouna, I. A., Rentzsch, K., Tryc, A. B., Dahm, L., et al. (2015) · Stroke · doi:10.1161/strokeaha.114.008323 · Cited by 90
“Mechanistic studies using murine transgenic models showed that APOE4 increases BBB susceptibility to injury(25) and leads to BBB breakdown and microvascular reductions in humanized transgenic APOE4knock-in mice compared with APOE3-knock-in mice.(26,27) The present study has been designed to test these hypotheses in pa…”
BackgroundObesity and sex interact in the regulation of Alzheimer's disease
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“Recent observations confirm that capillary function is disturbed prior to neurodegenerative changes in animal models of dementia (Bell et al., 2010; Bell et al., 2012), and we have pointed out that capillary morphology and function is likely to be disturbed in most AD risk factors, suggesting that capillary dysfunctio…”
BackgroundYamazaki, Y., Shinohara, M., Yamazaki, A., Ren, Y., Asmann, Y. W., Kanekiyo, T., & Bu, G. (2020) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.119.313169 · Cited by 89
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Cerebral Small Vessel Disease: a Review of the Pathophysiological Mechanisms
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“These vascular deficits precede the neuronal dysfunction and can initiate neurodegenerative changes [129].”
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“Moreover, it is reported that the different impacts of APOE subtypes on the outcomes of SAH may be due to their diverse affinity to the functional receptors [23, 24].”
BackgroundVázquez‐Rosa, E., Shin, M., Dhar, M., Chaubey, K., Cintrón-Pérez, C. J., Tang, X., Liao, X., Miller, E., Koh, Y., Barker, S., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2010430117 · Cited by 89
“The astrocyte-derived lipid transport molecule apolipoprotein-e (apoE) is a major factor that regulates BBB permeability, via regulation of low density lipoprotein receptor-related protein 1-cyclophilin A-matrix metalloproteinase-9 signaling in pericytes at the NVU (69).”
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“…etc. (Armulik et al., 2010; Daneman et al., 2010; Nitta et al., 2003; Vanlandewijck et al., 2018; Y. Zhang et al., 2014)), and down regulation of these components are often used as an indicator for TJ dysfunction (Alvarez et al., 2011; Bell et al., 2010; Bell et al., 2012; Zhong et al., 2008).”
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“Most recently, in 2012, APOE was found to trigger an inflammatory cascade that weakens the blood– brain barrier (BBB) through an inflammatory molecule known as cyclophilin A (CypA) (Bell et al. 2012).”
BackgroundBrain endothelial TAK1 and NEMO safeguard the neurovascular unit
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“Recent work on CNS pericytes has revealed an important role for these cells in various CNS disease states, including as BBB gatekeepers warding off neurodegeneration (Bell et al., 2010; Bell et al., 2012) and as major participants in the formation in the fibrotic scar following spinal cord and stroke-induced brain inj…”
BackgroundPrecision Nutrition for Alzheimer’s Prevention in ApoE4 Carriers
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“Using transgenic mice, Bell and colleagues [55] showed that ApoE3 protein, but not ApoE4 protein, can bind to the LRP1 receptor to inhibit CypA expression and reduce downstream NFκB and MMP9 activity, protecting BBB integrity.”
BackgroundThe old guard: Age-related changes in microglia and their consequences
Costa, J., Martins, S., Ferreira, P. A., Cardoso, A. M., Guedes, J. R., Peça, J., & Cardoso, A. L. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111512 · Cited by 88
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“Hospitalization, days, median (IQR) 17 (10-28) 29 (10-51) – –”
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“For example, the E4 variant of apolipoprotein E (APOE), the main susceptibility gene for AD, leads to accelerated BBBD and cognitive decline in humans and animals [63,64].”
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“The astrocytic detrimental effects on BBB after TBI could be explained by the release of vasoactive endothelial growth factor (Argaw et al.2009) or apolipoprotein E (Bell et al.2012) shown to exacerbate BBB damage.”
BackgroundGlial fibrillary acidic protein in Alzheimer’s disease: a narrative review
Leipp, F., Vialaret, J., Mohaupt, P., Coppens, S., Jaffuel, A., Niehoff, A., Lehmann, S., & Hirtz, C. (2024) · Brain Communications · doi:10.1093/braincomms/fcae396 · Cited by 93
“131 Dysregulation of calcium signalling and the release of inflammatory markers associated with neuroinflammation can also compromise BBB function by inducing the loss of tight junctions.”
Parikh, I. J., Guo, J., Chuang, K., Zhong, Y., Rempe, R. G., Hoffman, J. D., Armstrong, R., Bauer, B., Hartz, A. M. S., & Lin, A. (2016) · Aging · doi:10.18632/aging.101094 · Cited by 84
“Reduced CBF is linked to anxiety and depression [4-6], and impaired BBB is associated with neuroinflammation and synaptic dysfunction [7].”
BackgroundImaging the role of blood–brain barrier disruption in normal cognitive ageing
Verheggen, I. C. M., de Jong, J. J. A., van Boxtel, M. P. J., Postma, A. A., Jansen, J. F. A., Verhey, F. R. J., & Backes, W. H. (2020) · GeroScience · doi:10.1007/s11357-020-00282-1 · Cited by 85
Blood Biomarkers for Detection of Brain Injury in COVID-19 Patients
DeKosky, S. T., Kochanek, P. M., Valadka, A. B., Clark, R. S. B., Chou, S., Au, A. K., Horvat, C. M., Jha, R. M., Mannix, R., Wisniewski, S. R., et al. (2020) · Journal of Neurotrauma · doi:10.1089/neu.2020.7332 · Cited by 87
“ApoE4 is associated with increased risk of intracerebral hemorrhage (ICH)298 and predicts unfavorable neurological outcome after TBI and stroke.283,299 ApoE4 also appears to have direct effects on the cerebrovascular system and may affect neurovascular functions independently of its known influence on amyloid beta (Ab…”
BackgroundEndothelial BACE1 Impairs Cerebral Small Vessels via Tight Junctions and eNOS
Zhou, H., Gao, F., Yang, X., Lin, T., Li, Z., Wang, Q., Yao, Y., Li, L., Ding, X., Shi, K., et al. (2022) · Circulation Research · doi:10.1161/circresaha.121.320183 · Cited by 84
Self-citationNagata, T., Kobayashi, N., Ishii, J., Shinagawa, S., Nakayama, R., Shibata, N., Kuerban, B., Ohnuma, T., Kondo, K., Arai, H., et al. (2015) · Dementia and Geriatric Cognitive Disorders Extra · doi:10.1159/000375367 · Cited by 81
The pericyte–glia interface at the blood–brain barrier
Giannoni, P., Badaut, J., Dargazanli, C., De Maudave, A. F., Klement, W., Costalat, V., & Marchi, N. (2018) · Clinical Science · doi:10.1042/cs20171634 · Cited by 81
A Review on Tramiprosate (Homotaurine) in Alzheimer's Disease and Other Neurocognitive Disorders
Manzano, S., Agüera, L., Aguilar, M., & Olazarán, J. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.00614 · Cited by 82
“Besides, preclinical studies showed that the expression of ApoE4 is associated with activation of a pro-inflammatory pathway in pericytes and blood-brain barrier breakdown, leading to neuronal uptake of neurotoxic proteins, as well as reductions in the blood flow (21).”
BackgroundAPOE ɛ4 dose associates with increased brain iron and β-amyloid via blood–brain barrier dysfunction
Uchida, Y., Kan, H., Sakurai, K., Horimoto, Y., Hayashi, E., Iida, A., Okamura, N., Oishi, K., & Matsukawa, N. (2022) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2021-328519 · Cited by 84
A “multi-omics” analysis of blood–brain barrier and synaptic dysfunction in APOE4 mice
Barisano, G., Kisler, K., Wilkinson, B., Nikolakopoulou, A. M., Sagare, A. P., Wang, Y., Gilliam, W., Huuskonen, M. T., Hung, S.-T., Ichida, J. K., et al. (2022) · Journal of Experimental Medicine · doi:10.1084/jem.20221137 · Cited by 78
“…downregulates vascular endothelial growth factor, possibly protecting from vascular endothelial growth factor – induced BBB breakdown (Argaw et al., 2012); and Chuk and Nfkbia , NF-κ B inhibitors possibly suppressing the proinflammatory NF-κ B pathway linked to BBB breakdown (Bell et al., 2012).”
InfluentialSelf-citationDetrimental role of pericyte Nox4 in the acute phase of brain ischemia
Nishimura, A., Ago, T., Kuroda, J., Arimura, K., Tachibana, M., Nakamura, K., Wakisaka, Y., Sadoshima, J., Iihara, K., & Kitazono, T. (2015) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x15606456 · Cited by 79
“MMP-9 is a major metalloproteinase in the brain after brain ischemia(30) and may be produced from various cell types, including pericytes.(7) It is known that MMP-9 activation and subsequent BBB breakdown occur biphasically after brain ischemia: blood cell-derived MMP-9 participates in the early breakdown of BBB withi…”
BackgroundThe Links between Cardiovascular Diseases and Alzheimer's Disease
Leszek, J., Вячеславовна, М. Е., Belousov, D. M., Koutsouraki, E., Szczechowiak, K., Kobusiak−Prokopowicz, M., Mysiak, A., Diniz, B. S., Somasundaram, S. G., Kirkland, C. E., et al. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200729093724 · Cited by 93
“ApoE takes part in a variety of processes, including blood-brain barrier (BBB) integrity maintenance and cardiovascular disorders [128-131], immune and inflammation process regulation [127, 132, 133], the pathogenesis of infectious diseases [134], etc.”
BackgroundAstrocyte–Endotheliocyte Axis in the Regulation of the Blood–Brain Barrier
Pivoriūnas, A., & Verkhratsky, A. (2021) · Neurochemical Research · doi:10.1007/s11064-021-03338-6 · Cited by 85
APOE and neuroenergetics: an emerging paradigm in Alzheimer's disease
Wolf, A. B., Caselli, R. J., Reiman, E. M., & Valla, J. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.10.011 · Cited by 84
“Interestingly, apoE4 has been shown recently to contribute to breakdown of the blood brain barrier via effects on cyclophilin A, which could further affect energetics because of disruption of nutrient transport (Bell et al., 2012).”
BackgroundCrouch, E. E., Liu, C., Silva-Vargas, V., & Doetsch, F. K. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.1188-14.2015 · Cited by 83
Amyloid cross-seeding raises new dimensions to understanding of amyloidogenesis mechanism
Chaudhuri, P., Prajapati, K. P., Anand, B. G., Dubey, K., & Kar, K. (2019) · Ageing Research Reviews · doi:10.1016/j.arr.2019.100937 · Cited by 81
Ting, K. K., Coleman, P. R., Kim, H. J., Zhao, Y., Mulangala, J., Cheng, N. C., Li, W., Gunatilake, D., Johnstone, D. M., Loo, L., et al. (2023) · GeroScience · doi:10.1007/s11357-023-00927-x · Cited by 81
“Furthermore, APOE4 expression results in activation of pericytes through a cyclophilin A-dependent pathway and with vascular uptake of neurotoxic proteins, and cerebral blood flow reductions that precede neuronal dysfunction [10].”
BackgroundMethodInfluentialBasal lamina changes in neurodegenerative disorders
Nguyen, B., Bix, G., & Yao, Y. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00502-y · Cited by 75
“Similarly, activation of the same pathway in pericytes causes BBB breakdown in mice deficient in murine ApoE or those expressing human ApoE4, which poorly interacts with LRP1 [104].”
BackgroundInfluentialHampel, H. J., Schneider, L. S., Giacobini, E., Kivipelto, M., Sindi, S., Dubois, B., Broich, K., Nisticò, R., Aisen, P. S. S., & Lista, S. (2014) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2015.995637 · Cited by 82
“Since apoE4 is recognized to disrupt the blood–brain barrier integrity and to reduce small cerebral vessels [47], apoE is probably implicated in the maintenance of cognitive function by modulating the function of cerebrovascular systems.”
BackgroundZhang, J., Jiang, W., & Zuo, Z. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.12.034 · Cited by 75
“A recent study suggests that activation of cyclophilin A–NF-jB–MMP-9 signaling pathway in the pericytes contributes to the apolipoprotein E4-associated BBB breakdown (Bell et al., 2012).”
APOE and Alzheimer’s Disease: Neuroimaging of Metabolic and Cerebrovascular Dysfunction
Brandon, J. A., Farmer, B. C., Williams, H. C., & Johnson, L. A. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00180 · Cited by 75
“Importantly, these E4-associated vascular defects were observed as early as 2 weeks of age (Bell et al., 2012) well preceding the neuronal and synaptic dysfunction that is observed in these mice in late age.”
BackgroundAnti-amyloid-β protein agents for the treatment of Alzheimer’s disease: an update on emerging drugs
Lozupone, M., Solfrizzi, V., D’Urso, F., Di Gioia, I., Sardone, R., Dibello, V., Stallone, R., Liguori, A., Ciritella, C., Daniele, A., et al. (2020) · Expert Opinion on Emerging Drugs · doi:10.1080/14728214.2020.1808621 · Cited by 77
Divecha, Y. A., Rampes, S., Tromp, S., Boyanova, S., Fleckney, A. L., Fidanboylu, M., & Thomas, S. A. (2025) · Pharmacological Reviews · doi:10.1016/j.pharmr.2025.100052 · Cited by 83
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“As Tg2576 mice, apoE4 mice have BBB disruption at the age of 9 months (Bell et al., 2012), and signs of BBB impairment have been shown in humans carrying the apoE4 allele (Salloway et al., 2002).”
BackgroundPerkins, M., Wolf, A. B., Chavira, B., Shonebarger, D., Meckel, J. P., Leung, L., Ballina, L. E., Ly, S., Saini, A., Jones, T. B., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-151205 · Cited by 80
“A study of AD patients with reduced protein levels of GLUT1 indicated that mRNA levels were not impacted, pointing to possible alterations in posttranscriptional regulation [48].”
BackgroundXue, C., Sowden, M. P., & Berk, B. C. (2018) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.117.310661 · Cited by 74
“Zlokovic and our group showed that elevated iCypA concentrations in pericytes caused nuclear translocation of NF-κB and increased activation of MMP-9.(57) The intracellular CypA–NF-κB–MMP9 pathway in pericytes was associated with degradation of EC tight junctions and basement membrane, resulting in blood–brain barrier…”
BackgroundSelf-citationParodi‐Rullán, R. M., Javadov, S. A., & Fossati, S. (2021) · Cells · doi:10.3390/cells10112903 · Cited by 75
“In addition to the decreased expression of TJ proteins, which has been observed in AD [28,165], expression of matrix metalloproteinases (MMPs) has also been associated with increased BBB permeability [137,159,166,167].”
BackgroundZhang, Q., Song, Q., Yu, R., Wang, A., Jiang, G., Huang, Y., Chen, J., Xu, J., Wang, D., Chen, H., et al. (2023) · Advanced Science · doi:10.1002/advs.202204596 · Cited by 74
Emerging Roles of Endothelial Nitric Oxide in Preservation of Cognitive Health
Katusic, Z. S., d’Uscio, L. V., & He, T. (2023) · Stroke · doi:10.1161/strokeaha.122.041444 · Cited by 73
Yue, Q., & Hoi, M. P. M. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.367832 · Cited by 84
“A previous study investigating the relationship between AD astrocytic ApoE and pericytes showed that proinflammatory pathway cyclophilin (CypA)/NF-κB/MMP9 was activated in pericytes leading to BBB breakdown (Bell et al., 2012).”
Thomas, R., Zuchowska, P., Morris, A. W. J., Marottoli, F. M., Sunny, S., Deaton, R., Gann, P. H., & Tai, L. M. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0387-3 · Cited by 72
“In 9 and 12 months old APOE-TR mice lower microvessel coverage has been demonstrated [1, 4], although the effect of sex is unclear.”
BackgroundTraumatic brain injury results in acute rarefication of the vascular network
Obenaus, A., Ng, M. T., Orantes, A. M., Kinney‐Lang, E., Rashid, F. M., Hamer, M., DeFazio, R. A., Tang, J., Zhang, J. H., & Pearce, W. J. (2017) · Scientific Reports · doi:10.1038/s41598-017-00161-4 · Cited by 73
Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling
Kisler, K., Nikolakopoulou, A. M., Sweeney, M. D., Lazić, D., Zhao, Z., & Zloković, B. V. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00027 · Cited by 73
Vascular ApoE4 impairs behavior by modulating gliovascular function
Yamazaki, Y., Liu, C.-C., Yamazaki, A., Shue, F., Martens, Y. A., Chen, Y., Qiao, W., Kurti, A., Oue, H., Ren, Y., et al. (2021) · Neuron · doi:10.1016/j.neuron.2020.11.019 · Cited by 71
“, 1995), BBB dysfunction (Bell et al., 2012; Fullerton et al., 2001), and hypercholesterolemia are reported in the absence of murine apoE.”
BackgroundCurrent views on meningeal lymphatics and immunity in aging and Alzheimer’s disease
Rego, S., Sánchez, G., & Mesquita, S. D. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00645-0 · Cited by 79
“APOE4 mice show reduced blood vessel density and length, microvascular damage, loss of pericyte coverage, and signs of DNA fragmentation in both pericytes and blood endothelial cells; all indicative of exacerbated BBB breakdown [126].”
BackgroundCandela, P., Saint‐Pol, J., Kuntz, M., Boucau, M., Lamartinière, Y., Gosselet, F., & Fénart, L. (2014) · Brain Research · doi:10.1016/j.brainres.2014.10.047 · Cited by 78
Tryps and trips: cell trafficking across the 100-year-old blood–brain barrier
Bentivoglio, M., & Kristensson, K. (2014) · Trends in Neurosciences · doi:10.1016/j.tins.2014.03.007 · Cited by 78
Aragón-González, A., Shaw, P. J., & Ferraiuolo, L. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232315271 · Cited by 73
From degenerative disease to malignant tumors: Insight to the function of ApoE
Miao, G., Zhuo, D., Han, X. N., Yao, W., Liu, C., Liu, H., Cao, H., Sun, Y., Chen, Z., & Feng, T. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.114127 · Cited by 76
Wang, C., Lu, J., Sha, X., Qiu, Y., Chen, H., & Yu, Z. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-00935-z · Cited by 70
Talwar, P., Sinha, J., Grover, S., Rawat, C., Kushwaha, S. S., Agarwal, R., Taneja, V., & Kukreti, R. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9390-0 · Cited by 71
“In addition, decreased lipidation than APOE ε3 [117] and blood–brain barrier (BBB) breakdown causing reduction on cerebral blood flow [128, 129] was also observed in APOE ε4 carriers.”
BackgroundRisk factor for Alzheimer’s disease breaks the blood–brain barrier
Ishii, M., & Iadecola, C. (2020) · Nature · doi:10.1038/d41586-020-01152-8 · Cited by 69
Bangen, K. J., Preis, S. R., Delano‐Wood, L., Wolf, P. A., Libon, D. J., Bondi, M. W., Au, R., DeCarli, C. S., & Brickman, A. M. (2017) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0000000000000215 · Cited by 68
Addressing Blood–Brain Barrier Impairment in Alzheimer’s Disease
Sharma, C., Woo, H., & Kim, S. R. (2022) · Biomedicines · doi:10.3390/biomedicines10040742 · Cited by 72
Uchida, Y., Kan, H., Sakurai, K., Oishi, K., & Matsukawa, N. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1111448 · Cited by 70
The Effect of Systemic Chemotherapy on Neurogenesis, Plasticity and Memory
Wigmore, P. (2012) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2012_235 · Cited by 66
Pan, P., Zhao, H., Zhang, X., Li, Q., Qu, J., Zuo, S., Yang, F., Liang, G., Zhang, J. H., Liu, X., et al. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-1699-6 · Cited by 67
Dissecting the complexities of Alzheimer disease with in vitro models of the human brain
Blanchard, J., Victor, M. B., & Tsai, L. (2021) · Nature Reviews Neurology · doi:10.1038/s41582-021-00578-6 · Cited by 68
Chouinard‐Watkins, R., & Plourde, M. (2014) · Nutrients · doi:10.3390/nu6104452 · Cited by 73
“related proinflammatory pathway in the pericytes [121].”
BackgroundApoE Influences the Blood-Brain Barrier Through the NF-κB/MMP-9 Pathway After Traumatic Brain Injury
Teng, Z., Guo, Z., Zhong, J., Cheng, C., Huang, Z., Wu, Y., Tang, S., Luo, C., Peng, X., Wu, H., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-06932-3 · Cited by 68
Marottoli, F. M., Katsumata, Y., Koster, K. P., Thomas, R., Fardo, D. W., & Tai, L. M. (2017) · ASN NEURO · doi:10.1177/1759091417719201 · Cited by 69
“, 2011), or indirectly through peripheral and central processes (Bell et al., 2012; Casey et al., 2015; Halliday et al., 2015).”
BackgroundApoE Regulates the Development of Adult Newborn Hippocampal Neurons
Tensaouti, Y., Stephanz, E. P., Yu, T., & Kernie, S. G. (2018) · eNeuro · doi:10.1523/eneuro.0155-18.2018 · Cited by 71
The Role of Hypoxia-Inducible Factor 1 in Mild Cognitive Impairment
Iyalomhe, O., Swierczek, S. I., Enwerem, N. Y., Chen, Y., Adedeji, M. O., Allard, J. S., Ntekim, O. E., Johnson, S. M., Hughes, K., Kurian, P., et al. (2016) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-016-0440-6 · Cited by 64
“1991; Ishii and Haga 1975; McCaulley and Grush 2015), and may also involve disruption of the blood–brain barrier, especially in APOe4 homozygotes (Bell et al. 2012).”
BackgroundChowdhury, E. A., Noorani, B., Alqahtani, F., Bhalerao, A., Raut, S., Sivandzade, F., & Cucullo, L. (2021) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x20985946 · Cited by 77
“recently reported no difference in BBB permeability across wildtype control and humanized Alzheimer’s disease animal models,(142) in net contrast to previous findings.(116,143) Animal models of AD also had limited success in predicting clinical outcomes.”
ResultApolipoprotein E-Mimetic COG1410 Reduces Acute Vasogenic Edema following Traumatic Brain Injury
Cao, F., Jiang, Y., Wu, Y., Zhong, J., Liu, J., Qin, X., Chen, L., Vitek, M. P., Li, F., Xu, L., et al. (2015) · Journal of Neurotrauma · doi:10.1089/neu.2015.3887 · Cited by 69
Hagan, N., & Ben‐Zvi, A. (2014) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2014.12.006 · Cited by 70
Linking APOE-ε4, blood-brain barrier dysfunction, and inflammation to Alzheimer's pathology
Riphagen, J. M., Ramakers, I. H. G. B., Freeze, W. M., Pagen, L. H. G., Hanseeuw, B. J., Verbeek, M. M., Verhey, F. R. J., & Jacobs, H. I. L. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.09.020 · Cited by 66
Watanabe, I., Kuriyama, N., Miyatani, F., Nomura, R., Naka, S., Nakano, K., Ihara, M., Iwai, K., Matsui, D., Ozaki, E., et al. (2016) · Scientific Reports · doi:10.1038/srep38561 · Cited by 66
Sudre, C. H., Cardoso, M. J., Frost, C. D., Barnes, J., Barkhof, F., Fox, N. C., & Sebastien Ourselin, A. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.01.014 · Cited by 62
Michels, L., Warnock, G., Buck, A., Macauda, G., Leh, S. E., Kaelin, A. M., Riese, F., Meyer, R., Tuura, R., Höck, C., et al. (2015) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x15605847 · Cited by 63
“In mice expression of APOE4 but not E3 or E2 led to blood brain barrier dysfunction and CBF reductions.(51) Other factors by which APOE4 may cause changes in CBF are its interaction with mitochondrial function, and its influence on neuroinflammation, which have been reviewed in detail elsewhere.”
BackgroundTLR4 inhibitor TAK-242 attenuates the adverse neural effects of diet-induced obesity
Moser, V. A., Uchoa, M. F., & Pike, C. J. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1340-0 · Cited by 65
“The role of other mechanisms like vascular and microbiota changes in the effects of obesity on the brain cannot be ruled out and should be addressed in future studies, especially given that inflammation may be important in these systems as well [137, 138].”
BackgroundAPOE and dementia – resequencing and genotyping in 105,597 individuals
Rasmussen, K. L., Tybjærg‐Hansen, A., Nordestgaard, B. G., & Frikke‐Schmidt, R. (2020) · Alzheimer's & Dementia · doi:10.1002/alz.12165 · Cited by 64
BLOOD-BRAIN BARRIER PERMEABILITY IN AGING AND ALZHEIMER’S DISEASE
Rosenberg, G. A. (2014) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2014.25 · Cited by 63
Chernick, D., Ortiz‐Valle, S., Jeong, A., Qu, W., & Li, L. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.134306 · Cited by 64
Effects of Anserine/Carnosine Supplementation on Mild Cognitive Impairment with APOE4
Masuoka, N., Yoshimine, C., Hori, M., Tanaka, M., Asada, T., Abe, K., & Hisatsune, T. (2019) · Nutrients · doi:10.3390/nu11071626 · Cited by 63
Effects of APOE Genotype on Brain Proteomic Network and Cell Type Changes in Alzheimer's Disease
Dai, J., Johnson, E. C. B., Dammer, E. B., Duong, D. M., Gearing, M., Lah, J. J., Levey, A. I., Wingo, T. S., & Seyfried, N. T. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00454 · Cited by 62
“, 2014b) to examine endothelial cell type enrichment, given the known effects of ApoE polymorphism on vascular biology and cerebrovascular disease (Bell et al., 2012; Schilling et al., 2013; Tai et al., 2016; Bouchareychas and Raffai, 2018).”
BackgroundLoss of Endothelial Laminin α5 Exacerbates Hemorrhagic Brain Injury
Gautam, J., Miner, J. H., & Yao, Y. (2019) · Translational Stroke Research · doi:10.1007/s12975-019-0688-5 · Cited by 62
Beyond barrier functions: Roles of pericytes in homeostasis and regulation of neuroinflammation
Bhattacharya, A., Kaushik, D. K., Lozinski, B. M., & Yong, V. W. (2020) · Journal of Neuroscience Research · doi:10.1002/jnr.24715 · Cited by 63
“In this regard, it was earlier shown that MMP9, which has the potential to induce BBB breakdown, requires CypA-induced NFκB pathway activation in pericytes (Bell et al., 2012).”
BackgroundThe small HDL particle hypothesis of Alzheimer's disease
Martinez, A. E., Weissberger, G. H., Kuklenyik, Z., He, X., Meuret, C. J., Parekh, T., Rees, J. C., Parks, B. A., Gardner, M. S., King, S. M., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12649 · Cited by 63
Reconsidering the role of blood-brain barrier in Alzheimer’s disease: From delivery to target
Sousa, J. A., Bernardes, C., Bernardo-Castro, S., Lino, M. M., Albino, I., Ferreira, L., Brás, J., Guerreiro, R. J., Tábuas‐Pereira, M., Baldeiras, I., et al. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1102809 · Cited by 67
“RAGE blockage have showed to slow down Aβ pathology and lower the rate of cognitive decline in animal models (Bell et al., 2012).”
BackgroundPreis, L., Villringer, K., Brosseron, F., Düzel, E., Jessen, F., Petzold, G. C., Ramírez, A., Spottke, A. E., Fiebach, J. B., & Peters, O. (2024) · Alzheimer s Research & Therapy · doi:10.1186/s13195-024-01529-1 · Cited by 80
“APOE4-status has also been hypothesized as a risk factor for BBB-breakdown via activation of the Cyp-A-MMP9 pathway [60, 61] and has been associated with increased hippocampal BBB leakiness and higher sPDGFRβ [26].”
Background
Metadata
- Authors
- Bell, R. D., Winkler, E. A., Singh, I., Sagare, A. P., Deane, R., Wu, Z., Holtzman, D. M., Betsholtz, C., Armulik, A., Sallstrom, J., Berk, B. C., & Zlokovic, B. V.
- Affiliations
- University of Rochester Medicine (US)
- Washington University in St. Louis (US)
- Karolinska Institutet (SE)
- ORCID
- Venue
- Nature
- Published
- 2012-05-16
- Volume
- 485
- Issue
- 7399
- Pages
- 512-516
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4047116
- OpenAlex
- W2031762899
- Cited by
- 1,293
- References
- 35
- Citations by year
- 2026: 77 · 2025: 79 · 2024: 104 · 2023: 98 · 2022: 99 · 2021: 135 · 2020: 116 · 2019: 95 · 2018: 73 · 2017: 76 · 2016: 73 · 2015: 85 · 2014: 76 · 2013: 68 · 2012: 35
- FWCI
- 42.54
- Type
- journal article
- Language
- en
- Update notices
- correction (2023-05-05)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Institute on Aging (R01AG039452, R37AG023084, R37AG13956, R37AG23084, RF1AG039452, R37AG013956)
- National Institute of Neurological Disorders and Stroke (R37NS034467, R01NS034467, R37NS34467)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- APOE ε4, cyclophilin A, blood-brain barrier disruption, cerebrovascular integrity, MMP-9, NF-κB signaling, pericytes, cerebral blood flow, neurovascular dysfunction, Alzheimer's disease, neuroinflammation, cyclosporine, APOE isoforms, neurodegeneration, ApoE-deficient mice
- MeSH terms
- Animals, Apolipoproteins E, Blood-Brain Barrier, Cerebrovascular Circulation, Hippocampus, Humans, Mice, Transgenic, Microcirculation, Neurons, NF-kappa B, Neurodegenerative Diseases, Pericytes, Matrix Metalloproteinase 9, Cyclophilin A, Mice, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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