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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.
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“Whereas brain apoE plays a major role in brain amyloid metabolism, in blood‐brain barrier integrity, and in supplying cholesterol and phospholipids to neuronal cells, 12 , 13 , 14 , 16 , 30 , 31”
From APOE and dementia – resequencing and genotyping in 105,597 individuals (2020) · cites this paper as [12]
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In the citing paper
“Pericyte inflammation leads to neuronal uptake of neurotoxic proteins from the blood, and microvascular and cerebral blood flow reductions, which altogether subsequently lead to impaired clearance of amyloid-b [86,87].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [87]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“peripheral APOE seems to influence the brain partly by impacting the BBB.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [183]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“When compared with wild-type mice, both Apoe knockout mice and mice expressing APOE4 have a leaky BBB, a phenomenon also reported in cognitively unimpaired and mildly impaired individuals who carry an APOEε4 allele183–185.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [183]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“APOE4 alters the integrity of the blood brain barrier (BBB) influencing metabolite exchange between the periphery and the central nervous system (CNS) including reduced brain glucose and lipid transport [17][18][19] .”
From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [17]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“This hypothesis was the initial driver that defined a plethora of surprising functions of LDL receptor-related proteins (LRPs) in the central and peripheral nervous system (Bal et al., 2013; Beffert et al., 2005; Bell et al., 2012; Choi et al., 2013; Kim et al., 2008; Lane-Donovan and Herz, 2017; Liu et al., 2013; Liu et al., 2007; Liu et al., 2011; May et al., 2004; Nakajima et al., 2013; Pohl”
From Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease (2018) · cites this paper as Bell et al., 2012
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Transgenic expression of human APOE4 in the mice led to uncontrolled expression of proinflammatory cyclophilin A (CypA) in pericytes, inducing the activation of NF-kB and matrix metalloproteinase 9 (MMP9), which in turn results in BBB breakdown.183”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [183]
The cited source says what the claim attributes to it.
In the citing paper
“Transgenic mice lacking Apoe also develop an early BBB breakdown (60, 99, 147, 187, 226, 233, 406, 426, 437, 554), indicating that APOE is essential for maintaining BBB integrity.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
The cited source says what the claim attributes to it.
In the citing paper
“Additionally, LRP1 on pericytes regulates cerebrovascular integrity in an APOE-dependent fashion (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
The cited source says what the claim attributes to it.
In the citing paper
“On the other hand, APOE4 has a low affinity for LRP1, which activates CypA-MMP-9 pathway causing BBB breakdown (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
The cited source says what the claim attributes to it.
In the citing paper
“Transgenic mice expressing human APOE4 gene, but not APOE3 and APOE 2, develop an early BBB breakdown (60, 437), cerebral microhemorrhages (85), and loss of endothelial GLUT1 expression (9) that is followed by secondary neurodegenerative changes (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
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In the citing paper
“Inhibition of CypA-MMP-9 BBB degrading pathway by cyclosporine, a CypA inhibitor, restored BBB integrity and reversed secondary neurodegenerative changes in transgenic humanized APOE4 mice (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
The cited source says what the claim attributes to it.
In the citing paper
“These vascular changes precede neuronal dysfunction and neurodegeneration, but can be reversed by sealing the BBB (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [60]
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In the citing paper
“However, recent evidence indicates that apoE4 expression compromises the blood-brain barrier (as does apoE deficiency).40”
From Effects of the Absence of Apolipoprotein E on Lipoproteins, Neurocognitive Function, and Retinal Function (2014) · cites this paper as [40]
The cited source says what the claim attributes to it.
In the citing paper
“Both the level of apoE and apoE isoform plays a role: lack of murine Apoe protein as well as targeted replacement of murine Apoe with human apoE4, leads to blood-brain barrier breakdown by activating a proinflammatory cyclophilin A-nuclear factor kB-matrix metalloproteinase-9 pathway in pericytes [87].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [87]
The cited source says what the claim attributes to it.
In the citing paper
“vascular defects have been detected in human apoE4-targeted replacement (apoE4-TR) mice, but not apoE3-TR mice, at 2 weeks of age”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Bell et al 2012
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In the citing paper
“Moreover, as inflammatory factors including IL‐1, IL‐6, GM‐CSF, IL‐12 and IL‐23, and TNF‐α were all upregulated under AD condition.[ 23 ]”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [23]
Experimental — accuracy not yet measuredIn the citing paper
“inflammatory cell infiltrates were noted pathologically over 110 years ago in the penetrating arterioles and perivascular tissue in SVD,60 and consistently ever since (Figure 5, Supplementary Figure 3);19 plasma inflammatory markers are elevated in lacunar stroke56,127 and also associated genetically with WMH progression and lacunar infarcts.128”
From Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging (2013) · cites this paper as [127]
In the citing paper
“Activation of this pathway causes MMP-9-mediated degradation of endothelial tight junctions and basement membrane proteins, as shown in human ApoE4 targeted replacement mice (Bell et al., 2012).”
From The Pathobiology of Vascular Dementia (2013) · cites this paper as Bell et al., 2012
In the citing paper
“ApoE4, a major genetic risk factor for AD, leads to BBB disruption through a proinflammatory pathway involving cyclophilin A in pericytes (Bell et al., 2012).”
From The Pathobiology of Vascular Dementia (2013) · cites this paper as Bell et al., 2012
In the citing paper
“Of note, APOE4 also triggered inflammatory cascades, leading to neurovascular dysfunction, degeneration of the BBB, consequent penetration of toxic proteins from blood into the brain and reduced length of small blood vessels [466].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [466]
In the citing paper
“ApoE4 may also mediate neuropathological effects by directly modulating BBB integrity”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Bell et al., 2012
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Citations
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“In support of this idea, a recent study showed that APOE-deficient (Apoe−/−) mice with transgenic expression of human APOE4 show increased BBB permeability relative to Apoe−/− mice expressing human APOE2 or APOE3, and that this correlates with accelerated neurodegeneration (Bell et al., 2012).”
RetractedKanyenda, L. J., Verdile, G., Martins, R. N., Meloni, B. P., Chieng, J., Mastaglia, F. L., Laws, S. M., Anderton, R. S., & Boulos, S. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-131442 · Cited by 16
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Apolipoprotein E isoform dependently affects Tat-mediated HIV-1 LTR transactivation
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“Interestingly, increased levels of cyclophilin A and MMP-9 in endothelial cells and pericytes of cerebral microvessels were found in patients with Alzheimer’s disease who carry the APOE4 gene; those correlated with BBB breakdown [100].”
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sdf1 Expression Reveals a Source of Perivascular-Derived Mesenchymal Stem Cells in Zebrafish
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APOE-Targeted Therapeutics for Alzheimer's Disease
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“Transgenic APOE-e4 mouse models suggest that APOE-e4 relates to more extensive BBB breakdown because of upregulation of metalloproteinase 9.(4) Vasodilation factors function at the neurovascular unit,(26,27) so damage to the BBB, a core component of the neurovascular unit, may result in a weakened dilatory response an…”
InfluentialFrank, C. J., & McNay, E. C. (2021) · Journal of Neuroendocrinology · doi:10.1111/jne.13074 · Cited by 16
“…prefrontal cortex and cerebrospinal fluid.100 The complexity of the interrelation between metabolic Topic Reference Finding Montagne et al. (2021)74, Bell et al. (2012)93, Halliday et al. (2016)94 APOE4 accelerated BBB dysfunction is dependent on the cyclophilin A/MMP9 pathway and independent of…”
BackgroundAPOE ε4 and late-life cognition: mediation by structural brain imaging markers
Ma, Y., Sajeev, G., VanderWeele, T. J., Viswanathan, A., Sigurdsson, S. O., Eiríksdóttir, G., Aspelund, T., Betensky, R. A., Grodstein, F., Albert Hofman, D., et al. (2022) · European Journal of Epidemiology · doi:10.1007/s10654-022-00864-7 · Cited by 15
“The major mechanism of ε4 is thought to be its effect on amyloidbeta accumulation (Aβ) in the brain [2] Increasing evidence also suggests that APOE ε4 expression may, independent of its effects on Aβ, lead to neuronal injury through multiple mechanisms such as activating proinflammatory processes, promoting blood-brai…”
BackgroundLi, T., Li, D., Wei, Q., Shi, M., Xiang, J., Gao, R., Chen, C., & Xu, Z. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106114 · Cited by 17
Bei, J., Miranda-Morales, E. G., Gan, Q., Qiu, Y., Husseinzadeh, S., Liew, J. Y., Chang, Q., Krishnan, B., Gaitas, A., Yuan, S., et al. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230347 · Cited by 18
Liu, L., Liang, J., Liu, Y.-H., Liu, B., Dong, X., Cai, W.-H., & Zhang, N. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e30523 · Cited by 15
“Furthermore, the binding of ApoE4 to the low-density lipoprotein receptor-related protein 1 (LRP1) receptor has been shown to downregulate the expression of Apolipoprotein A, leading to increased cell stress activated through the NF-kB pathway in surrounding cells [109].”
BackgroundRetractedEmerging microglial biology highlights potential therapeutic targets for Alzheimer's disease
Fan, X., Chen, H., He, W., & Zhang, J. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102471 · Cited by 16
Investigating the Interplay between Cardiovascular and Neurodegenerative Disease
Cousineau, J., Dawe, A. M., & Alpaugh, M. (2024) · Biology · doi:10.3390/biology13100764 · Cited by 15
“…activation [363] ↑ Memory impairments [363,364] CAD ApoE − / − G ↑ Atherosclerotic lesions [342], cardiac hypertrophy [365] ↑ BBB permeability [366,367] ↑ Memory impairments [368] CAD Ldlr − / − G ↓ Diastolic blood pressure, Cardiomyopathy [369] & ↑ Atherosclerotic lesions [370] ↑ BBB…”
contributors, T. M., Boltze, J., Kleinschnitz, C., Reymann, K. G., Reiser, G., Wagner, D., Kranz, A., & Michalski, D. (2012) · Experimental & Translational Stroke Medicine · doi:10.1186/2040-7378-4-14 · Cited by 15
“While extending this perspective by glial cells, recent research yielded that different isoforms of apolipoprotein E, originating from astrocytes, have opposite effects on the release of matrix metalloproteinase-9 (MMP-9), an enzyme known to mediate BBB breakdown [12].”
BackgroundRisk factors for amyloid positivity in older people reporting significant memory concern
Zhang, J., Zhou, W., Cassidy, R. M., Su, H., Su, Y., & Zhang, X. (2017) · Comprehensive Psychiatry · doi:10.1016/j.comppsych.2017.09.015 · Cited by 17
“Importantly, BBB breakdown also leads to impaired amyloid-β clearance, and oligaemia in turn increases amyloid-β production [45].”
BackgroundResultInfluentialVgontzas, A., & Renthal, W. R. (2018) · The American Journal of Medicine · doi:10.1016/j.amjmed.2018.07.041 · Cited by 15
Joseph, C. R. (2021) · Diagnostics · doi:10.3390/diagnostics11101888 · Cited by 15
Малашенкова, И. К., Krynskiy, S., Mamoshina, M. V., & Didkovsky, N. A. (2018) · Medical Immunology (Russia) · doi:10.15789/1563-0625-2018-3-303-312 · Cited by 17
Vascular Health is Associated with Amyloid-β in Cognitively Normal Older Adults
Liu, Y., Perdomo, S. J., Ward, J. L., Vidoni, E. D., Sisante, J. F., Kirkendoll, K., Burns, J. M., & Billinger, S. A. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-181268 · Cited by 15
“APOE appears key to maintaining cerebrovas439 cular integrity independent of A deposition [53], 440 and the APOE4 allele may accelerate blood-brain bar441 rier degradation [54].”
BackgroundThe characteristics of brain atrophy prior to the onset of Alzheimer’s disease: a longitudinal study
Hu, Y., Zhu, T., & Zhang, W. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1344920 · Cited by 16
Sex-dependent gut microbiota-brain-cognition associations: a multimodal MRI study
Zhang, S., Cai, H., Wang, C., Zhang, C., Zhao, W., Zhang, T., Zhang, B., Chen, J., Liu, S., Zhu, J., et al. (2023) · BMC Neurology · doi:10.1186/s12883-023-03217-3 · Cited by 15
“Impaired BBB function is also linked with CBF alterations [58].”
BackgroundApolipoprotein ε in Brain and Retinal Neurodegenerative Diseases
Abyadeh, M., Gupta, V., Paulo, J. A., Sheriff, S., Shadfar, S., Fitzhenry, M. J., Amirkhani, A., Gupta, V. B., Salekdeh, G. H., Haynes, P. A., et al. (2023) · Aging and Disease · doi:10.14336/ad.2023.0312-1 · Cited by 15
“(CypA–NF-kB–MMP9) pathway in pericytes however ApoE4 but not ApoE2, ApoE3 and mice ApoE, were inefficient in controlling CypA expression in pericytes leading to higher levels of MMP9 and consequently BBB breakdown [172, 173].”
Research Progress on the Mechanisms of Protocatechuic Acid in the Treatment of Cognitive Impairment
Liang, S., Zhao, Z.-M., Liu, L., Zhang, Y., & Liu, X. (2024) · Molecules · doi:10.3390/molecules29194724 · Cited by 16
Epithelial cells supply Sonic Hedgehog to the perinatal dentate gyrus via transport by platelets
Choe, Y., Huynh, T., & Pleasure, S. J. (2015) · eLife · doi:10.7554/elife.07834 · Cited by 16
“In pathological conditions in which the cerebrovascular integrity is perturbed such as neuroinflammatory diseases and Alzheimer’s diseases (Bell et al., 2012; Sengillo et al., 2012), taking advantages of platelets as a vehicle to transfer druggable materials into the leaky area may become a translational approach.”
BackgroundRNA-Seq Mouse Brain Regions Expression Data Analysis: Focus on ApoE Functional Network
Babenko, V. N., Смагин, Д. А., & Kudryavtseva, N. N. (2017) · Berichte aus der medizinischen Informatik und Bioinformatik/Journal of integrative bioinformatics · doi:10.1515/jib-2017-0024 · Cited by 13
“While stated earlier [40], this is the first report of highly significant Apoe-LRP1 covariation based on RNA-Seq data, elucidating the major receptor counterpart for ApoE across brain regions.”
BackgroundResultDisease-Induced Alterations in Brain Drug Transporters in Animal Models of Alzheimer’s Disease
Vellonen, K., Ihalainen, J. A., Boucau, M., Gosselet, F., Picardat, T., Gynther, M., Kanninen, K. M., White, A. R., Malm, T., Koıstınaho, J., et al. (2017) · Pharmaceutical Research · doi:10.1007/s11095-017-2263-7 · Cited by 15
Haemodynamic impairment along the Alzheimer’s disease continuum
Diomedi, M., Rocco, A., Bonomi, C. G., Mascolo, A. P., Lucia, V. D., Marrama, F., Sallustio, F., Koch, G., & Martorana, A. (2021) · European Journal of Neurology · doi:10.1111/ene.14834 · Cited by 14
Oligomeric and fibrillar amyloid beta 42 induce platelet aggregation partially through GPVI
Elaskalani, O., Khan, I., Morici, M., Matthysen, C. P., Sabale, M., Martins, R. N., Verdile, G., & Metharom, P. (2017) · Platelets · doi:10.1080/09537104.2017.1401057 · Cited by 17
“These findings have implications for understanding how platelets contribute to the pathologies observed in AD and in particular CAA.”
BackgroundInfluentialMilenković, D., Krga, I., Dinel, A., Morand, C., Layé, S., & Castanon, N. (2021) · Journal of Functional Foods · doi:10.1016/j.jff.2021.104609 · Cited by 14
New Approaches to Profile the Microbiome for Treatment of Neurodegenerative Disease
Elmaleh, D. R., Downey, M. A., Kundakovic, L., Wilkinson, J. E., Neeman, Z., & Segal, E. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210198 · Cited by 14
“Transgenic APOE mouse models of AD show that astrocyte-derived APOE4 involves the inflammatory cytokine cyclophilin A (CypA) to induce BBB dysfunction through activation of a CypA—NF-κ B—MMP-9 signaling pathway that causes neurovascular deficits and may initiate neurodegeneration [53].”
Immunometabolism Reframes Alzheimer’s Disease: From Systemic Dysmetabolism to Glial Rewiring
Bach, D., & Nguyen, L. L. (2026) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-026-01691-0 · Cited by 15
“In humans and models, pericyte injury (including APOE4-CypA-MMP9 signaling) correlates with BBB leakiness and cognitive decline (Bell et al. 2012; Nation et al. 2019; Montagne et al. 2021).”
Reduced endothelial caveolin-1 underlies deficits in brain insulin signalling in type 2 diabetes
Shetti, A., Ramakrishnan, A., Romanova, L. G., Li, W., Vo, K., Volety, I., Ratnayake, I. S., Stephen, T. K. L., Minshall, R. D., Cologna, S. M., et al. (2023) · Brain · doi:10.1093/brain/awad028 · Cited by 13
Stamenković, S., Li, Y., Waters, J., & Shih, A. Y. (2023) · Stroke · doi:10.1161/strokeaha.122.037156 · Cited by 14
Bai, Y., Mi, W., Meng, X., Dong, B., Jiang, Y., Lu, Y., & Yu, Y. (2023) · BMC Neuroscience · doi:10.1186/s12868-023-00795-3 · Cited by 14
Lendvai-Emmert, D., Magyar-Sümegi, Z. D., Hegedus, E., Szarka, N., Fazekas, B., Amrein, K., Czeiter, E., Büki, A., Ungvari, Z. I., & Tóth, P. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1252796 · Cited by 13
“The ApoE-cyclophilin pathway was shown (9) to activate NF-kB in pericytes, which transcriptionally activates the gelatinase MMP-9 in cerebral vessels, leading to degradation of capillary basement membrane and tight junction proteins and ultimately BBB disruption (9, 27–29).”
BackgroundInfluentialMatsuo, K., & Nishihara, H. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.390978 · Cited by 14
“BBB breakdown detected by decreased tight junction protein and leakage of 40 kDa dextran and IgG was already seen in 2-week-old APOE4 mice (Bell et al., 2012), when neuronal density, expression levels of pre-or postsynaptic proteins, and cortical neural activity were still normal.”
BackgroundGastfriend, B. D., Snyder, M. E., Holt, H., Daneman, R., Palecek, S. P., & Shusta, E. V. (2024) · Science Advances · doi:10.1126/sciadv.adi1737 · Cited by 16
“Brain mural cells are also implicated in the pathogenesis of neurological disorders including Alzheimer’s disease ( 19 – 21 ) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) ( 22 , 23 ).”
Eivazzadeh‐Keihan, R., Dogari, H., Ahmadpour, F., Aliabadi, H. A. M., Radinekiyan, F., Maleki, A. R., Fard, L. S., Tahmasebi, B., Mojdehi, M. F., & Mahdavi, M. R. (2021) · Scientific Reports · doi:10.1038/s41598-021-92919-0 · Cited by 13
Ng, K. F., Anderson, S., Mayo, P., Aung, H. H., Walton, J. H., & Rutledge, J. C. (2015) · Magnetic Resonance in Medicine · doi:10.1002/mrm.25985 · Cited by 12
Association between APOE4 and biomarkers in cerebral adrenoleukodystrophy
Orchard, P. J., Markowski, T. W., Higgins, L., Raymond, G. V., Nascene, D. R., Miller, W. P., Pierpont, E. I., & Lund, T. C. (2019) · Scientific Reports · doi:10.1038/s41598-019-44140-3 · Cited by 13
Developing Trojan horses to induce, diagnose and suppress Alzheimer’s pathology
Aziz, A. A., & Amtul, Z. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104471 · Cited by 12
Neely, B. A., Ferrante, J. A., Chaves, J. M., Soper, J. L., Almeida, J. S., Arthur, J. M., Gulland, F. M. D., & Janech, M. G. (2015) · PLoS ONE · doi:10.1371/journal.pone.0123295 · Cited by 13
“A study in transgenic mice demonstrated that human ApoE2/3 forms help to maintain the blood brain barrier when murine ApoE was deleted [36].”
BackgroundMelatonin: Therapeutic Intervention in Mild Cognitive Impairment and Alzheimer Disease
Grandy, J. K. (2013) · Journal of Neurology & Neurophysiology · doi:10.4172/2155-9562.1000148 · Cited by 13
“A recent study demonstrated that APOE-ε4 directly damages blood vessels in the blood brain barrier and that this neurovascular damage decreases Aβ clearance from the brain [9].”
BackgroundHyperglycemia-induced blood-brain barrier dysfunction: Mechanisms and therapeutic interventions
Chen, C., Xu, X., Lu, J., Xiang, Y., Shi, L., & Liu, D. (2025) · Microvascular Research · doi:10.1016/j.mvr.2025.104820 · Cited by 14
Translating Alzheimer’s Disease Mechanisms into Therapeutic Opportunities
Li, J., Wang, L., Zhang, X., Shi, J., Zhu, Y. Z., Wang, H., Zhu, X., Zhu, Q., & Luo, J. (2025) · Biomolecules · doi:10.3390/biom15091290 · Cited by 13
“Moreover, the vascular anomalies in APOE ε 4-deficient and APOE ε 4-overexpressing animals predate neural impairment and may instigate neurodegenerative alterations through the cyclophilin A signaling pathway in the pericytes of cerebral blood arteries, which operates independently of A β [10].”
Wang, Y., Zhang, M., & Li, W. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.10.018 · Cited by 13
“Astrocyte-secreted apoli-poprotein E3 (APOE3) suppressed the cyclophilin A (CYPA) — nuclear factor-κ B (NF-κ B) — matrix-metalloproteinase-9 (MMP9) pathway in pericytes through a lipoprotein receptor, thus counter-acting the BBB disruption associated with apolipoprotein E4 (APOE4) 13 .”
InfluentialUnderly, R. G., & Shih, A. Y. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2020.619230 · Cited by 12
Estudillo, E., López-Ornelas, A., Rodríguez-Oviedo, A., Cruz, N. G. D. L., Vargas-Hernández, M. A., & Jiménez, A. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.373672 · Cited by 14
“The action of cyclosporine was proposed to be on MMP-9 derived from pericytes (Bell et al., 2012); whether cyclosporine could also act on BECs to decrease thrombin or fibrin in brain parenchyma is unknown.”
BackgroundAPOE ε4 Gene Carriers Demonstrate Reduced Retinal Capillary Densities in Asymptomatic Older Adults
Zhang, Z., Kwapong, W. R., Cao, L., Feng, Z., Wu, B. C., Liu, J., & Zhang, S. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12175649 · Cited by 12
“Previous model reports demonstrated that APOE ε4 affects microvascular density and neurovascular regulation [5,34].”
Cai, J., Xie, D., Kong, F., Zhai, Z., Zhu, Z., Zhao, Y., Xu, Y., & Sun, T. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-231249 · Cited by 13
“CypA, a pro-inflammatory cytokine, has been previously demonstrated to be damaging to the vascular system of APOE mice withaorticaneurysmsandatherosclerosis[93].”
InfluentialErickson, M. A., Johnson, R. S., Damodarasamy, M., MacCoss, M. J., Keene, C. D., Banks, W. A., & Reed, M. J. (2024) · Fluids and Barriers of the CNS · doi:10.1186/s12987-024-00581-1 · Cited by 12
“Peptidyl-prolyl cis–trans isomerase A (PPIA), otherwise known as cyclophilin A, was previously shown to be upregulated in pericytes and to promote BBB leakage via inflammatory and matrix metalloproteinase (MMP) activation, particularly in humanized APOE4 mice [64].”
BackgroundIron chelation by oral deferoxamine treatment decreased brain iron and iron signaling proteins
Thorwald, M. A., Godoy-Lugo, J. A., Maria, N. S., Chakhoyan, A., O’Day, P. A., Jacobs, R., Zloković, B. V., & Finch, C. E. (2025) · Journal of Alzheimer s Disease · doi:10.1177/13872877241313031 · Cited by 12
“4 Because these EFAD mice have weaker BBB integrity, 44 and ApoE alleles in fl uence BBB integrity, 45 it was important to know how WT mice respond to DFO.”
Davidson, M. H., Szarek, M., Scheltens, P., Vijverberg, E., Hsieh, A., Ditmarsch, M., Kling, D., Curcio, D., Nicholls, S. J., Ray, K. K., et al. (2026) · The Journal of Prevention of Alzheimer's Disease · doi:10.1016/j.tjpad.2025.100394 · Cited by 16
“Improved vascular health is particularly relevant for APOE4 carriers, who exhibit greater atherosclerosis, microvascular damage, and compromise of BBB integrity, making them especially susceptible to vascular contributions to cognitive impairment [44,45].”
Human brain organoids in Alzheimer’s disease
Kang, Y. J., & Cho, H. (2021) · Organoid · doi:10.51335/organoid.2021.1.e5 · Cited by 13
Ito, J., & Michikawa, M. (2014) · Journal of Lipids · doi:10.1155/2014/530720 · Cited by 12
“Interestingly, recent studies have shown that apoE regulates BBB formation to control the integrity of tight junctions of BBB in an apoE-isoform-dependent manner in vitro and in vivo [21, 22].”
BackgroundBlood–Brain Barrier Transport of Alzheimer’s Amyloid β-Peptide
Nelson, A. R., Sagare, A. P., & Zloković, B. V. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802173-6.00009-5 · Cited by 12
Self-citationGao, L., Jiang, Y., Wei, S., Shang, S., Li, P., Chen, C., Dang, L., Wang, J., Huo, K., Deng, M., et al. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180399 · Cited by 12
“APOE4 may also activate a pro-inflammatory pathway in the brain, resulting in subsequent neuronal dysfunction and impaired integrity of the BBB [39, 40].”
Wan, X., Gan, C., You, C., Fan, T., Zhang, S., Zhang, H., Wang, S., Shu, K., Wang, X., & Lei, T. (2019) · Journal of neurosurgery · doi:10.3171/2019.4.jns183472 · Cited by 12
Li, M., Sun, H., Shen, T., Xue, S., Zhao, Y. W., Leng, B., Zhang, J., Li, Z., & Xia, Z. (2021) · Sleep Medicine · doi:10.1016/j.sleep.2021.10.009 · Cited by 12
Strategies for blood–brain barrier rejuvenation and repair
Searson, P. C., & Banks, W. A. (2026) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01364-5 · Cited by 15
Huang, Z. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-221042 · Cited by 12
ApoE Mimetic Peptides as Therapy for Traumatic Brain Injury
Laskowitz, D. T., & Wyck, D. W. V. (2023) · Neurotherapeutics · doi:10.1007/s13311-023-01413-0 · Cited by 12
“…protein (LRP1) may initiate a signaling cascade [66–70] that are critical in mediating its immunomodulatory properties via mitogen-activated protein kinase (MAP kinase) pathways [71–73], and stabilization of the blood–brain barrier through the cyclophilin A-matrix metallopeptidase-9 pathway [74].”
BackgroundDeregulation of the Glymphatic System in Alzheimer’s Disease: Genetic and Non-Genetic Factors
Hu, Y., Su, T., Wu, L., Wu, J., Liu, D., Zhu, L., & Yuan, M. (2024) · Aging and Disease · doi:10.14336/ad.2023.1229 · Cited by 15
Liu, Q., Li, J., Cheng, X., Chen, G., Zhang, Y., Tian, Z., Wang, Y., Wang, H., Guo, X., Li, H., et al. (2024) · Environmental Research · doi:10.1016/j.envres.2024.119148 · Cited by 11
Yuan, Z., Li, X., Hao, Z., Tang, Z., Yao, X., & Wu, T. (2024) · Scientific Reports · doi:10.1038/s41598-024-62712-w · Cited by 16
“In addition, the biomarker testing was applied to monitor the state of AD progression by measuring the concentration of specific antibodies and proteins, including Aβ1-41, Aβ42/Aβ40, total tau protein (t-tau), and hyperphosphorylated tau protein (p-tau) in the cerebrospinal fluid or blood 10,11 .”
MethodCerebral microvascular changes in healthy carriers of the APOE-ɛ4 Alzheimer's disease risk gene
Aamand, R., Rasmussen, P. M., Andersen, K. S., de Paoli, S., Weitzberg, E., Christiansen, M., Lund, T. E., & Østergaard, L. (2024) · PNAS Nexus · doi:10.1093/pnasnexus/pgae369 · Cited by 11
“Our findings are consistent with earlier findings of reduced microvascular density in the neocortex, corpus callosum (55) and hippocampus (64, 65) of mice carrying the human APOE-ɛ 4 gene.”
ResultPerdaens, O., & Pesch, V. V. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252312637 · Cited by 12
Trivedi, A. A., Tercovich, K. G., Casbon, A.-J., Raber, J., Lowell, C. A., & Noble‐Haeusslein, L. J. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105430 · Cited by 10
“Disruption of the BBB, in turn, is linked to adverse pro-inflammatory events (Erickson and Banks, 2013) and contributes to the secondary pathogenesis as seen in a variety of neurodegenerative diseases (Bell et al., 2012; Najjar et al., 2017; Rosenberg, 2012; Zlokovic, 2008).”
Becker, G., Debatisse, J., Rivière, M., Silva, C. C. D., Beaudoin‐Gobert, M., Eker, O., Wateau, O., Cho, T., Wiart, M., Tremblay, L., et al. (2023) · Neurotherapeutics · doi:10.1007/s13311-023-01368-2 · Cited by 12
“Cyclosporine A has been shown to prevent BBB breakdown by blocking the cyclophilin A pathway in the pericytes and thereby protecting the neuro-vascular unit [14, 15].”
BackgroundSong, W., Peng, Z., Gooyit, M., Suckow, M. A., Schroeder, V. A., Wolter, W. R., Lee, M., Ikejiri, M., Cui, J., Gu, Z., et al. (2013) · ACS Chemical Neuroscience · doi:10.1021/cn400077d · Cited by 11
Sex-Specific MicroRNAs in Neurovascular Units in Ischemic Stroke
Florijn, B., Bijkerk, R., Kruyt, N., van Zonneveld, A. V., & Wermer, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111888 · Cited by 13
“This promotes a tight barrier whose maintenance is regulated by other NVU cells like neurons that secrete Wnt ligands [47], astrocytes which produce extracellular matrix (ECM) factors [48] and pericytes which promote endothelial quiescence [49].”
BackgroundFang, X. (2018) · Metabolic Brain Disease · doi:10.1007/s11011-018-0239-x · Cited by 11
Blood-brain barrier at the interface of air pollution-associated neurotoxicity and neuroinflammation
Young, T. L., Zychowski, K. E., Denson, J. L., & Campen, M. J. (2018) · Advances in neurotoxicology · doi:10.1016/bs.ant.2018.10.010 · Cited by 11
Wang, X., Xiao, D., Ma, C., Zhang, L., Duan, Q., Zheng, X., Mao, M., Zhu, D., & Li, Q. (2019) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2019.01.005 · Cited by 11
Alzheimer's disease phenotype based upon the carrier status of the apolipoprotein E ɛ4 allele
Ji, X., Peng, X., Tang, H., Pan, H., Wang, W. D., Wu, J., Chen, J., & Wei, N. (2023) · Brain Pathology · doi:10.1111/bpa.13208 · Cited by 9
“In APOE knock-in and glial fibrillary acidic protein promoter transgenic mice, it was found that APOE4 activated the proinflammatory cytokines cyclophilin A in pericytes and NF-KB/matrix metalloproteinase-9 signaling pathways, thereby increasing susceptibility to BBB impairment [74].”
BackgroundThe Role of RIN3 Gene in Alzheimer’s Disease Pathogenesis: a Comprehensive Review
Meshref, M. M., Ghaith, H. S., Hammad, M. A., Shalaby, M. M. M., Ayasra, F., Monib, F. A., Attia, M. S., Ebada, M. A., Elsayed, H., Shalash, A., et al. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03802-0 · Cited by 12
“LRP1 is a key amyloid-β clearance acceptor that also binds to APOE [137].”
BackgroundWei, W., Sun, H., Yang, B. V., Song, E., & Song, Y. (2024) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.3c00728 · Cited by 10
Zhang, Z., Lin, W., Gan, Q., Lei, M., Gong, B., Zhang, C., Henrique, J. S., Han, J., Tian, H., Tao, Q., et al. (2024) · Angiogenesis · doi:10.1007/s10456-024-09946-4 · Cited by 10
“To determine the lengths of CD31-positive cerebrovascular profiles, we followed the methodology previously reported by [21].”
The effects of doxorubicin on blood-brain barrier integrity in hCMEC/D3
Patel, C., Glytsou, C., Jang, M.-H., & Cole, P. D. (2025) · NeuroToxicology · doi:10.1016/j.neuro.2025.103355 · Cited by 10
“For example, increased cyclophilin A signaling in pericytes has been linked with an increase in BBB breakdown in Apolipoprotein E4 (ApoE4) mice (Bell et al., 2012) possibly responsible for neurodegeneration.”
Kidoikhammouan, S., Seubwai, W., Tantapotinan, N., Silsirivanit, A., Wongkham, S., Sawanyawisuth, K., & Wongkham, C. (2012) · PubMed · Cited by 10
Hong, F., Mu, X., Ze, Y., Li, W., Zhou, Y., & Ji, J. (2021) · Journal of Biomedical Nanotechnology · doi:10.1166/jbn.2021.3083 · Cited by 10
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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