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Apolipoprotein E controls cerebrovascular integrity via cyclophilin A
Open accessAbstract
Human apolipoprotein E has three isoforms: APOE2, APOE3 and APOE4. APOE4 is a major genetic risk factor for Alzheimer's disease and is associated with Down's syndrome dementia and poor neurological outcome after traumatic brain injury and haemorrhage. Neurovascular dysfunction is present in normal APOE4 carriers and individuals with APOE4-associated disorders. In mice, lack of Apoe leads to blood-brain barrier (BBB) breakdown, whereas APOE4 increases BBB susceptibility to injury. How APOE genotype affects brain microcirculation remains elusive. Using different APOE transgenic mice, including mice with ablation and/or inhibition of cyclophilin A (CypA), here we show that expression of APOE4 and lack of murine Apoe, but not APOE2 and APOE3, leads to BBB breakdown by activating a proinflammatory CypA-nuclear factor-κB-matrix-metalloproteinase-9 pathway in pericytes. This, in turn, leads to neuronal uptake of multiple blood-derived neurotoxic proteins, and microvascular and cerebral blood flow reductions. We show that the vascular defects in Apoe-deficient and APOE4-expressing mice precede neuronal dysfunction and can initiate neurodegenerative changes. Astrocyte-secreted APOE3, but not APOE4, suppressed the CypA-nuclear factor-κB-matrix-metalloproteinase-9 pathway in pericytes through a lipoprotein receptor. Our data suggest that CypA is a key target for treating APOE4-mediated neurovascular injury and the resulting neuronal dysfunction and degeneration.
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“In a transgenic mouse carrying human APOE4 (a major genetic risk factor for AD), APOE4 secreted from astrocytes was found to bind with LRP1 on pericytes and induce uncontrollably proinflammatory CypA expression in pericytes, inducing the activation of NF-kB and matrix metalloproteinase 9 (MMP9),183,501”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [183]
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In the citing paper
“In addition, reduced expression of tight junction proteins was found in AD mouse model with increased MMP9 activities.183”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [183]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“For example, astrocytes secrete apolipoprotein E (APOE) to signal pericytes via low-density lipoprotein receptor-related protein-1 (LRP1), which suppress the activation of cyclophilin A (CypA)-matrix metalloproteinase 9 (MMP-9) BBB-degrading pathway, while in the absence of murine APOE mouse pericytes produce active MMP-9 causing BBB breakdown (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Studies in transgenic mice expressing human APOE isoforms have shown that astrocyte-secreted APOE2 and APOE3 bind to LRP1 on pericytes in vivo, which inhibits the proinflammatory CypA-MMP-9 pathway preventing degradation of BBB TJ and basement membrane proteins (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“APOE exerts toxic effects on the cerebrovascular system (694) and neurons (383, 384) and influences A 𝛃 clearance (60, 64, 98, 135, 256, 266, 278, 294, 315, 693), amyloid deposition (39, 256, 258, 266, 278, 314, 518, 612), and tau-related neurodegeneration (533) in an allele-dependent manner APOE4 > APOE3 > APOE2 .”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
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“Apoe -/ -mice also develop secondary neurodegenerative changes after BBB breakdown in the absence of A 𝛃 pathology (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Neuroinflammation is another key hallmark in AD brain.[ 23 ]”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [23]
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In the citing paper
“Together this comprises a disease spectrum likely linked by deposition of amyloid-β in arterioles in the central nervous system combined with degradation of the blood-brain barrier, which collectively leaves a frail intracerebral vasculature prone to atherosclerotic cerebrovascular disease [17,31,32].”
From APOE and vascular disease: Sequencing and genotyping in general population cohorts (2023) · cites this paper as [17]
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In the citing paper
“apoE is a central apolipoprotein in cerebral cholesterol metabolism and is involved in brain amyloid metabolism, blood brain barrier integrity, and transport of various lipid species to neuronal cells [15][16][17][18][19].”
From APOE and vascular disease: Sequencing and genotyping in general population cohorts (2023) · cites this paper as [17]
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In the citing paper
“The similar findings presently observed for rare APOE variants with low apoE may reflect that the intracerebral vasculature, brain tissue and blood-brain barrier are dependent on normal levels of apoE for sufficient local lipid transport and βamyloid clearance [17,18,31,43].”
From APOE and vascular disease: Sequencing and genotyping in general population cohorts (2023) · cites this paper as [17]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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
“Transgenic expression of human APOE4 in the mice led to uncontrolled expression of proinflammatory cyclophilin A (CypA) in pericytes, inducing the activation of NF-kB and matrix metalloproteinase 9 (MMP9), which in turn results in BBB breakdown.183”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [183]
The cited source says what the claim attributes to it.
In the citing paper
“Transgenic mice lacking Apoe also develop an early BBB breakdown (60, 99, 147, 187, 226, 233, 406, 426, 437, 554), indicating that APOE is essential for maintaining BBB integrity.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
The cited source says what the claim attributes to it.
In the citing paper
“Additionally, LRP1 on pericytes regulates cerebrovascular integrity in an APOE-dependent fashion (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
The cited source says what the claim attributes to it.
In the citing paper
“On the other hand, APOE4 has a low affinity for LRP1, which activates CypA-MMP-9 pathway causing BBB breakdown (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
The cited source says what the claim attributes to it.
In the citing paper
“Transgenic mice expressing human APOE4 gene, but not APOE3 and APOE 2, develop an early BBB breakdown (60, 437), cerebral microhemorrhages (85), and loss of endothelial GLUT1 expression (9) that is followed by secondary neurodegenerative changes (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
The cited source says what the claim attributes to it.
In the citing paper
“Inhibition of CypA-MMP-9 BBB degrading pathway by cyclosporine, a CypA inhibitor, restored BBB integrity and reversed secondary neurodegenerative changes in transgenic humanized APOE4 mice (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
The cited source says what the claim attributes to it.
In the citing paper
“These vascular changes precede neuronal dysfunction and neurodegeneration, but can be reversed by sealing the BBB (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
The cited source says what the claim attributes to it.
In the citing paper
“However, recent evidence indicates that apoE4 expression compromises the blood-brain barrier (as does apoE deficiency).40”
From Effects of the Absence of Apolipoprotein E on Lipoproteins, Neurocognitive Function, and Retinal Function (2014) · cites this paper as [40]
The cited source says what the claim attributes to it.
In the citing paper
“Both the level of apoE and apoE isoform plays a role: lack of murine Apoe protein as well as targeted replacement of murine Apoe with human apoE4, leads to blood-brain barrier breakdown by activating a proinflammatory cyclophilin A-nuclear factor kB-matrix metalloproteinase-9 pathway in pericytes [87].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [87]
The cited source says what the claim attributes to it.
In the citing paper
“vascular defects have been detected in human apoE4-targeted replacement (apoE4-TR) mice, but not apoE3-TR mice, at 2 weeks of age”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Bell et al 2012
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In the citing paper
“Moreover, as inflammatory factors including IL‐1, IL‐6, GM‐CSF, IL‐12 and IL‐23, and TNF‐α were all upregulated under AD condition.[ 23 ]”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [23]
Experimental — accuracy not yet measuredIn the citing paper
“inflammatory cell infiltrates were noted pathologically over 110 years ago in the penetrating arterioles and perivascular tissue in SVD,60 and consistently ever since (Figure 5, Supplementary Figure 3);19 plasma inflammatory markers are elevated in lacunar stroke56,127 and also associated genetically with WMH progression and lacunar infarcts.128”
From Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging (2013) · cites this paper as [127]
In the citing paper
“Activation of this pathway causes MMP-9-mediated degradation of endothelial tight junctions and basement membrane proteins, as shown in human ApoE4 targeted replacement mice (Bell et al., 2012).”
From The Pathobiology of Vascular Dementia (2013) · cites this paper as Bell et al., 2012
In the citing paper
“ApoE4, a major genetic risk factor for AD, leads to BBB disruption through a proinflammatory pathway involving cyclophilin A in pericytes (Bell et al., 2012).”
From The Pathobiology of Vascular Dementia (2013) · cites this paper as Bell et al., 2012
In the citing paper
“Of note, APOE4 also triggered inflammatory cascades, leading to neurovascular dysfunction, degeneration of the BBB, consequent penetration of toxic proteins from blood into the brain and reduced length of small blood vessels [466].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [466]
In the citing paper
“ApoE4 may also mediate neuropathological effects by directly modulating BBB integrity”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Bell et al., 2012
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Citations
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“Remarkably, the BBB impairment in these mice could be reversed by SB-3CT treatment and specific inhibition ofMMP-9, but not of MMP-2 (63).”
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“Previous studies suggest that APOE4 is a major genetic risk factor for AD and poor neurological outcomes after traumatic brain injury and hemorrhage (Bell et al., 2012).”
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BackgroundSelf-citationAge-Related Changes in the Behavior of Apolipoprotein E Knockout Mice
Fuentes, D., Fernández, N., García, Y., García, T. E., Morales, A., & Menéndez, R. (2018) · Behavioral Sciences · doi:10.3390/bs8030033 · Cited by 44
“In addition to vascular changes, ApoE knock-out mice exhibit an age-dependent breakdown of the BBB, which correlates with behavioral impairments [61,62].”
BackgroundThe pleiotropic vasoprotective functions of high density lipoproteins (HDL)
Boyce, G. K., Button, E. B., Sonja, S. V., & Wellington, C. L. (2017) · Journal of Biomedical Research · doi:10.7555/jbr.31.20160103 · Cited by 41
“[151] Bell RD, Winkler EA, Singh I, et al.”
BackgroundTargeting Apolipoprotein E for Alzheimer’s Disease: An Industry Perspective
Suidan, G. L., & Ramaswamy, G. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20092161 · Cited by 42
“role in lipid transport to neurons [11,12], synaptogenesis [13], cerebrovascular integrity and cerebral blood flow (CBF) [14,15], hippocampal neurogenesis [16], neuroimmune modulation [17] and amyloid clearance [18,19].”
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Unified theory of Alzheimer’s disease (UTAD): implications for prevention and curative therapy
Nehls, M. (2016) · Journal of Molecular Psychiatry · doi:10.1186/s40303-016-0018-8 · Cited by 41
“In ApoE4-expressing animal models, those vascular defects precede neuronal dysfunction and can initiate neurodegenerative changes [48].”
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Self-citationBlood–brain barrier dysfunction in mice induced by lipopolysaccharide is attenuated by dapsone
Zhou, T., Zhao, L., Zhan, R., He, Q., Tong, Y., Tian, X., Wang, H., Zhang, T., Fu, Y., Sun, Y., et al. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.09.093 · Cited by 40
Compensating for synaptic loss in Alzheimer’s disease
Abuhassan, K., Coyle, D., Belatreche, A., & Maguire, L. (2013) · Journal of Computational Neuroscience · doi:10.1007/s10827-013-0462-8 · Cited by 43
Genetic mouse models to study blood–brain barrier development and function
Sohet, F., & Daneman, R. (2013) · Fluids and Barriers of the CNS · doi:10.1186/2045-8118-10-3 · Cited by 43
“demonstrated a rescue of the aforementioned phenotypes suggesting that the over-expression of cypA in the ApoE knockout mice was important for the BBB dysfunction [115].”
BackgroundInfluentialvon Willebrand factor contributes to poor outcome in a mouse model of intracerebral haemorrhage
Zhu, X., Cao, Y., Wei, L., Cai, P., Xu, H., Luo, H., Bai, X., Lu, L., Liu, J., Fan, W., et al. (2016) · Scientific Reports · doi:10.1038/srep35901 · Cited by 41
Thomas, R., Morris, A. W. J., & Tai, L. M. (2017) · Heliyon · doi:10.1016/j.heliyon.2017.e00319 · Cited by 41
“However, evidence suggests that APOE4 induces cognitive [35, 36, 37] and cerebrovascular deficits, including higher leakiness and lower vessel coverage [32, 33], in the absence of high Aβ levels.”
BackgroundInfluentialGustafsson, S. S., Lindström, V., Ingelsson, M., Hammarlund‐Udenaes, M., & Syvänen, S. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.08.002 · Cited by 39
“However, as studies of APOE4 animal models also show cerebrovascular changes and altered NVU properties, the impact of APOE on small molecular drug transport needs further evaluation in both animals and humans (Bell et al., 2012; Alata et al., 2015).”
Influence of Matrix Metallopeptidase 9 on Beta-Amyloid Elimination Across the Blood-Brain Barrier
Shackleton, B., Ringland, C., Abdullah, L. I., MULLAN, M. J., Crawford, F., & Bachmeier, C. J. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-01672-z · Cited by 40
Pericytes for Therapeutic Approaches to Ischemic Stroke
Cao, L., Zhou, Y., Chen, M., Li, L., & Zhang, W. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.629297 · Cited by 41
Crossing borders in Alzheimer’s disease: A T cell’s perspective
van Olst, L., Coenen, L., Nieuwland, J. M., Rodriguez-Mogeda, C., de Wit, N. M., Kamermans, A., Middeldorp, J., & de Vries, H. E. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114398 · Cited by 45
Wasielewska, J. M., Chaves, J. C. S., Johnston, R. L., Milton, L. A., Hernández, D., Chen, L., Song, J. H., Lee, W., Leinenga, G., Nisbet, R. M., et al. (2022) · Theranostics · doi:10.7150/thno.72685 · Cited by 41
“Studies in transgenic mice further support a role for APOE4 in BBB dysfunction, reflected by early BBB breakdown and cerebral microhemorrhages, which lead to secondary neurodegeneration [8, 11-13].”
BackgroundChang, Y., Fennema‐Notestine, C., Holland, D., McEvoy, L. K., Stricker, N. H., Salmon, D. P., Dale, A. M., Bondi, M. W., & Initiative, A. D. N. (2014) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2013.05.1763 · Cited by 39
Afsar, A., Castro, M. D. C. C., Soladogun, A. S., & Li, Z. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24087258 · Cited by 45
Choriocapillaris reduction accurately discriminates against early‐onset Alzheimer's disease
Kwapong, W. R., Tang, F., Liu, P., Zhang, Z., Cao, L., Feng, Z., Yang, S., Shu, Y., Xu, H., Lu, Y., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13871 · Cited by 39
“57,58 Our SS-OCTA analysis revealed a sparser SVP, DCP, and choriocapillaris in APOE ε 4 carriers compared to non-carriers.”
BackgroundJeon, S. Y., Byun, M. S., Yi, D., Lee, J. H., Choe, Y. M., Ko, K., Sohn, B. K., Choi, H. J., Lee, J., & Lee, D. Y. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.11.001 · Cited by 42
Dalkara, T. (2019) · Stroke · doi:10.1161/strokeaha.118.023590 · Cited by 40
Tokgöz, S., & Claassen, J. A. H. R. (2021) · Cardiology and Therapy · doi:10.1007/s40119-020-00209-z · Cited by 42
“The APOE e4 allele alters the permeability of the blood–brain barrier, which may result in increased levels of Ab in the peripheral system of carriers compared to non-carriers [50].”
BackgroundKirchner, K., Garvert, L., Kühn, A. L., Bonk, S., Grabe, H. J., & der Auwera, S. V. (2023) · Cells · doi:10.3390/cells12212512 · Cited by 39
“For instance, treatment of ApoE ε 4 mice with the immunosuppressive intracellular CypA-binding drug cyclosporine A indicated that BBB changes are reversible and cyclosporine A might be a promising drug approach to prevent bApoE ε 4-induced BBB breakdown [11].”
BackgroundInfluentialKotredes, K. P., Pandey, R. S., Persohn, S. A., Elderidge, K., Burton, C. P., Miner, E. W., Haynes, K. A., dos Santos, D. F. D. S., Williams, S. G., Heaton, N., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13828 · Cited by 39
The vascular contribution of apolipoprotein E to Alzheimer’s disease
Chen, F., Zhao, J., Meng, F., He, F., Ni, J., & Fu, Y. (2024) · Brain · doi:10.1093/brain/awae156 · Cited by 39
Blood-brain barrier and innate immunity in the pathogenesis of Alzheimer's disease
Šimić, G., Španić, E., Horvat, L. L., & Hof, P. R. (2019) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2019.06.003 · Cited by 40
Bangen, K. J., Thomas, K. R., Weigand, A. J., Sanchez, D. L., Delano‐Wood, L., Edmonds, E. C., Carmichael, O. T., Schwarz, C. G., Brickman, A. M., & Bondi, M. W. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.10.016 · Cited by 38
ApoE mimetic improves pathology and memory in a model of Alzheimer’s disease
Krishnamurthy, K., Cantillana, V., Wang, H., Sullivan, P. M., Kolls, B. J., Ge, X., Lin, Y., Mace, B., & Laskowitz, D. T. (2020) · Brain Research · doi:10.1016/j.brainres.2020.146685 · Cited by 39
Lanz, M., Janeiro, M. H., Milagro, F. I., Puerta, E., Ludwig, I. A., Pineda‐Lucena, A., Ramírez, M. J., & Solas, M. (2022) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2022.111668 · Cited by 40
Astrocytes: The Stars in Neurodegeneration?
Dittlau, K. S., & Freude, K. (2024) · Biomolecules · doi:10.3390/biom14030289 · Cited by 39
“In AD, APOE ε 4 carriers display pericyte degeneration due to insufficient astrocyte suppression of proinflammatory pathways, consequently damaging the BBB [215,216].”
Zheng, M., Wei, J., Tang, Y., Yang, C., Wei, Y., Yin, X., & Liu, Q. (2014) · Journal of Molecular Neuroscience · doi:10.1007/s12031-014-0291-x · Cited by 37
Inflammation as a Possible Link Between Dyslipidemia and Alzheimer’s Disease
Oliveira, B. C. D. L., Bellozi, P. M. Q., Reis, H. J., & de Oliveira, A. C. P. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.02.012 · Cited by 39
Sattiraju, A., & Mintz, A. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-16908-4_2 · Cited by 36
Kriaučiūnaitė, K., Kaušylė, A., Pajarskienė, J., Tunaitis, V., Lim, D., Verkhratsky, A., & Pivoriūnas, A. (2020) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-020-00871-w · Cited by 40
The Role of HDL and HDL Mimetic Peptides as Potential Therapeutics for Alzheimer’s Disease
Chernick, D., Zhong, R., & Li, L. (2020) · Biomolecules · doi:10.3390/biom10091276 · Cited by 39
Blood-Brain Barrier Disruption: A Common Driver of Central Nervous System Diseases
Segura‐Collar, B., Mata-Martínez, P., Hernández‐Laín, A., Sánchez‐Gómez, P., & Gargini, R. (2021) · The Neuroscientist · doi:10.1177/1073858420985838 · Cited by 39
Marottoli, F. M., Trevino, T. N., Geng, X. H., Arbieva, Z. H., Kanabar, P. N., Maienschein‐Cline, M., Lee, J. C., Lutz, S. E., & Tai, L. M. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.668296 · Cited by 38
Delicate regulation of IL-1β-mediated inflammation by cyclophilin A
Yang, W., Bai, X., Luan, X., Min, J., Tian, X., Li, H., Li, H., Sun, W., Liu, W., Fan, W., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110513 · Cited by 41
Epidemiology of neurodegeneration in American-style professional football players
Lehman, E. J. (2013) · Alzheimer s Research & Therapy · doi:10.1186/alzrt188 · Cited by 39
“Such studies not only would assist in identifying those at risk for developing a neurodegenerative disease but also may help in providing targeted thera peutic treatments among susceptible individuals [58].”
BackgroundPharmacological mTOR inhibitors in ameliorating Alzheimer’s disease: current review and perspectives
Xie, P.-L., Zheng, M.-Y., Han, R., Chen, W., & Mao, J.-H. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1366061 · Cited by 40
Sun, B., Li, L., Harris, O. A., & Luo, J. (2025) · Translational Neurodegeneration · doi:10.1186/s40035-025-00478-5 · Cited by 44
Can insulin signaling pathways be targeted to transport Aβ out of the brain?
Vandal, M., Bourassa, P., & Calon, F. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00114 · Cited by 37
“…series of BBB defects, including impaired Aβ clearance (Deane et al., 2008; Salem et al., 2015), reduced glucose and polyunsaturated fatty acids uptake, decreased microvascularization and CBF (Reiman et al., 2004; Bell et al., 2012; Sagare et al., 2012; Vandal et al., 2014a; Alata et al., 2015).”
Nock, T. G., Chouinard‐Watkins, R., & Plourde, M. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2017.07.004 · Cited by 37
Lucero, J., Suwannasual, U., Herbert, L. M., McDonald, J. D., & Lund, A. K. (2017) · Inhalation Toxicology · doi:10.1080/08958378.2017.1357774 · Cited by 37
“Utilizing this particular animal model presents limitations, as the Apo E protein is involved in the structural integrity and transport across the BBB (Bell et al., 2012; Nishitsuji et al., 2011).”
BackgroundApolipoprotein E as a novel therapeutic neuroprotection target after traumatic spinal cord injury
Cheng, X., Zheng, Y., Bu, P., Qi, X., Fan, C., Li, F., Kim, D., & Cao, Q. (2017) · Experimental Neurology · doi:10.1016/j.expneurol.2017.10.014 · Cited by 38
“In the present study, we used apoE peptide, COG112, which is designed by fusion of apoE133-149 with a protein transduction domain antennapedia (Antp) to enhance blood-brain barrier (BBB) and cell membrane penetration.”
BackgroundResultInfluentialDubey, H., Gulati, K., & Ray, A. (2018) · Reviews in the Neurosciences · doi:10.1515/revneuro-2017-0049 · Cited by 36
Pokhilko, A. V., Brezzo, G., Handunnetthi, L., Heilig, R., Lennon, R., Smith, C., Allan, S. M., Granata, A., Sinha, S., Wang, T., et al. (2021) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x211004307 · Cited by 35
Apolipoprotein E isoform-dependent effects on the processing of Alzheimer's amyloid-β
Chai, A. B., Lam, H. H. J., Kockx, M., & Gelissen, I. C. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2021.158980 · Cited by 41
Viña, D., Seoane, N., Vasquez, E. C., & Campos‐Toimil, M. (2021) · Cells · doi:10.3390/cells10081951 · Cited by 39
“Likewise, it has been experimentally shown that apolipoprotein E (APOE), a risk factor for AD, activates the pro-inflammatory cyclophilin A-nuclear factor-κM-matrix-metalloproteinase-9 pathway in pericytes, leading to BBB impairment [19].”
BackgroundHammer, C., Zerche, M., Schneider, A., Begemann, M., Nave, K., & Ehrenreich, H. (2014) · Molecular Psychiatry · doi:10.1038/mp.2014.52 · Cited by 37
Hajjar, I., Sorond, F., & Lipsitz, L. A. (2015) · Journal of the American Geriatrics Society · doi:10.1111/jgs.13235 · Cited by 37
“Mice models suggest that APOE-e4 disrupts BBB integrity through cyclophilin A.(12) As reviewed recently, most of the observations regarding APOE and cerebral microvascular effects were derived from animal models or postmortem studies; few human in vivo studies exist.”
BackgroundSaxena, S., Lai, I. K., Li, R., & Maze, M. (2019) · British Medical Bulletin · doi:10.1093/bmb/ldz010 · Cited by 37
Interaction between APOE genotype and diabetes in cognitive decline
Shinohara, M., Tashiro, Y., Suzuki, K., Fukumori, A., Bu, G., & Sato, N. (2020) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12006 · Cited by 36
Caselli, R. J., Knopman, D. S., & Bu, G. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12124 · Cited by 36
Perkins, J. D., Wilkins, S. S., Kamran, S., & Shuaib, A. M. (2021) · Neurobiology of Stress · doi:10.1016/j.ynstr.2021.100332 · Cited by 38
Sex differences in Alzheimer’s disease: plasma MMP-9 and markers of disease severity
Tsiknia, A. A., Sundermann, E. E., Reas, E. T., Edland, S. D., Brewer, J. B., Galasko, D. R., Banks, S. J., & Initiative, A. D. N. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-01106-4 · Cited by 39
“Furthermore, studies have demonstrated that MMP-9 effects on blood-brain barrier damage depend on APOE ε4 [50, 51], which has been shown to have a stronger effect on AD pathology and clinical outcomes in women [52–54].”
BackgroundXu, W., Bai, Q., Dong, Q., Guo, M., & Cui, M. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.870674 · Cited by 38
Barnes, A., Ballerini, L., Hernández, M. D. C. V., Chappell, F. M., Maniega, S. M., Meijboom, R., Backhouse, E. V., Stringer, M. S., Coello, R. D., Brown, R., et al. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.889884 · Cited by 34
Lee, J., Lee, H., Lee, H. G., Shin, M., Shin, M.-G., Seo, J., Lee, E. J., Park, S. A., & Park, S. (2023) · Nature Communications · doi:10.1038/s41467-023-44319-3 · Cited by 37
Extracellular Proteolysis of Apolipoprotein E (apoE) by Secreted Serine Neuronal Protease
Tamboli, I. Y., Heo, D., & Rebeck, G. W. (2014) · PLoS ONE · doi:10.1371/journal.pone.0093120 · Cited by 35
The blood brain barrier: Insights from development and ageing
Delaney, C. P., & Campbell, M. (2017) · Tissue Barriers · doi:10.1080/21688370.2017.1373897 · Cited by 36
“Pericytic low density lipoprotein receptor-related protein-1 (LRP1) binds ApoE and inhibits downstream cyclophillin A, preventing Nf-kB and subsequent MMP9 upregulation.(84) On comparison between ApoE isoforms, ApoE4 was the sole isoform unable to induce this Nf-kB repression resulting in an increase in MMP9 and degra…”
BackgroundValkenburgh, J. S. V., Meuret, C. J., Martinez, A. E., Kodancha, V., Solomon, V. A., Chen, K., & Yassine, H. N. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.700847 · Cited by 38
Novak, V. (2012) · Current Cardiovascular Risk Reports · doi:10.1007/s12170-012-0260-2 · Cited by 36
“More studies are needed to determine whether these results translate into neurodegeneration in humans [104].”
BackgroundDirectional Fluid Transport across Organ–Blood Barriers: Physiology and Cell BiologyPreprint
Caceres, P. S., Benedicto, I., Lehmann, G. L., & Rodriguez-Boulan, E. J. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a027847 · Cited by 35
“Moreover, astrocytes control the production of matrix metalloproteinase 9 by pericytes, which can degrade the basement membrane and promote the degradation of TJ proteins in ECs (Bell et al. 2012).”
BackgroundRole for apolipoprotein E in neurodegeneration and mercury intoxication
Lopez, M. E. C. (2017) · Frontiers in Bioscience-Elite · doi:10.2741/e819 · Cited by 35
“Different ApoE isoforms are also responsible for differences in the integrity of the blood-brain barrier in mouse models (53).”
BackgroundMural cell-derived laminin-α5 plays a detrimental role in ischemic stroke
Nirwane, A. M., Johnson, J., Nguyen, B., Miner, J. H., & Yao, Y. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0676-8 · Cited by 34
“To further determine if laminin-α5 expression is abrogated in mural cells in α5-PKO mice, we isolated primary mural cells from control and α5-PKO brains using a well-established protocol [9, 26, 78] and examined laminin-α5 expression in these cells.”
MethodKrishnan, M., Hwang, J. S., Kim, M. K., Kim, Y. J., Seo, J. H., Jung, J., & Ha, E. (2020) · Nutrients · doi:10.3390/nu12020471 · Cited by 34
Metadata
- Authors
- Bell, R. D., Winkler, E. A., Singh, I., Sagare, A. P., Deane, R., Wu, Z., Holtzman, D. M., Betsholtz, C., Armulik, A., Sallstrom, J., Berk, B. C., & Zlokovic, B. V.
- Affiliations
- University of Rochester Medicine (US)
- Washington University in St. Louis (US)
- Karolinska Institutet (SE)
- ORCID
- Venue
- Nature
- Published
- 2012-05-16
- Volume
- 485
- Issue
- 7399
- Pages
- 512-516
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4047116
- OpenAlex
- W2031762899
- Cited by
- 1,293
- References
- 35
- Citations by year
- 2026: 77 · 2025: 79 · 2024: 104 · 2023: 98 · 2022: 99 · 2021: 135 · 2020: 116 · 2019: 95 · 2018: 73 · 2017: 76 · 2016: 73 · 2015: 85 · 2014: 76 · 2013: 68 · 2012: 35
- FWCI
- 42.54
- Type
- journal article
- Language
- en
- Update notices
- correction (2023-05-05)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Institute on Aging (R01AG039452, R37AG023084, R37AG13956, R37AG23084, RF1AG039452, R37AG013956)
- National Institute of Neurological Disorders and Stroke (R37NS034467, R01NS034467, R37NS34467)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- APOE ε4, cyclophilin A, blood-brain barrier disruption, cerebrovascular integrity, MMP-9, NF-κB signaling, pericytes, cerebral blood flow, neurovascular dysfunction, Alzheimer's disease, neuroinflammation, cyclosporine, APOE isoforms, neurodegeneration, ApoE-deficient mice
- MeSH terms
- Animals, Apolipoproteins E, Blood-Brain Barrier, Cerebrovascular Circulation, Hippocampus, Humans, Mice, Transgenic, Microcirculation, Neurons, NF-kappa B, Neurodegenerative Diseases, Pericytes, Matrix Metalloproteinase 9, Cyclophilin A, Mice, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2
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