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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]
Experimental — accuracy not yet measured
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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]
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 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
“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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BackgroundInitiative, A. D. N., Wang, J., Peng, G., Liu, P., Tan, X., & Luo, B. (2019) · Cognitive Neurodynamics · doi:10.1007/s11571-019-09536-x · Cited by 10
High HbA1c level is correlated with blood-brain barrier disruption in syphilis patients
Wang, F., Ge, H., Su, X., Wang, R., Zeng, J., & Miao, J. (2019) · Neurological Sciences · doi:10.1007/s10072-019-04031-x · Cited by 9
mTOR: Alzheimer's disease prevention for APOE4 carriers
Lin, A., Butterfield, D. A., & Richardson, A. G. (2016) · Oncotarget · doi:10.18632/oncotarget.10349 · Cited by 9
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“Post mortem studies on brain tissue of APOE ε4 carriers [44], APOE4 transgenic mice [45], and other BBB co-culture models based on human APOE ε4-carrying hiPSCs [7], however, suggest that additional NVU cells, especially PCs, mediate structural changes and dysregulation of BCECs.”
BackgroundLin, C., Zhao, P., Sun, G., Liu, N., & Ji, J. (2024) · The FASEB Journal · doi:10.1096/fj.202401117r · Cited by 8
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Traumatic Brain Injury and Alzheimer’s Disease: A Shared Neurovascular Hypothesis
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Cerebral hypoperfusion, brain structural integrity, and cognitive impairment in older APOE4 carriers
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“Experiments in humanized APOE4 transgenic animals suggest that vascular effects of APOE4 include cerebral hypoperfusion injury [12, 13].”
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Rudman, M. D., Ulrich, J. D., & Holtzman, D. M. (2026) · Cell · doi:10.1016/j.cell.2026.06.006 · Cited by 12
Self-citationEndothelial Cell APOE3 Regulates Neurovascular, Neuronal, and Behavioral Function
Marottoli, F. M., Zhang, H., Flores-Barrera, E., de la Villarmois, E. A., Damen, F. C., Fernández, A. M. M. M., Blesson, H. V., Chaudhary, R., Nguyen, A. L., Nwokeji, A. E., et al. (2023) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.123.319816 · Cited by 7
“Astrocyte-produced apoE3 is thought to bind LRP1 on pericytes initiating a cascade that suppresses MMP9 production to limit basement membrane and tight junction degradation 13 and lower endothelial cell permeability in vitro.”
Gutiérrez‐Jiménez, E., Rasmussen, P. M., Mikkelsen, I. K., Kura, S., Fruekilde, S. K., Hansen, B. B., Bordoni, L., Carlsen, J., Palmfeldt, J., Boas, D. A., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70023 · Cited by 9
“We also measured CypA molecular signature, linked to microvasculardamage,includingBBBbreakdown, 66 andassessedplas-matic levels of VEGF-A, an essential pro-angiogenic factor associated with capillary stalling.”
Marotta, F., Marcellino, M. G., Solimene, U., Cuffari, B., Yadav, H., Khokhlov, A. N., Lorenzetti, A., Mantello, A., Cervi, J., & Catanzaro, R. (2017) · Clinical Pharmacology & Biopharmaceutics · doi:10.4172/2167-065x.1000170 · Cited by 8
“Recent studies using transgenic mice have shown the importance of proinflammatory Cyclophilin A (CypA)-metalloproteinase-9 in blood-brain-barrier integrity [9] while other have proved that a specific inhibitor of CyPA could reduce neuroinflammation, improve motor neurons activity and prolong survival in a mouse model…”
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“The CypA-NF-κB-MMP-9 Pathway Was Activated in EBI Stage After SAH A previous study showed that the CypA-NF-κB-MMP-9 pathway can regulate the integrity of the BBB via affecting the interactions between endothelial cells and pericytes (20).”
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“The CypA-MMP-9 pathway was previously demonstrated to be activated by ApoE4, which lead to the breakdown of BBB and, as a result, the neuronal uptake of multiple blood-derived neurotoxic proteins and microvascular and cerebral blood flow reductions in the pericytes of mice, and these changes preceded neuronal and syna…”
BackgroundHuo, C., Chen, M., Hour, T., Huang, L., Fong, Y.-O., Kuo, Y., Yang, Y., & Chuu, C. (2022) · Brain Sciences · doi:10.3390/brainsci12091134 · Cited by 8
“Elevation of CypA activates a pro-inflammatory pathway which leads to the BBB breakdown [13].”
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“Decreases in neuronal activity have been reported in young APOE4 mice, 14 and neuronal hyper-activity in old APOE4 mice.”
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“Previous evidence found that BBB breakdown may be linked to Apolipoprotein E 4 allele (ApoE4), the major genetic risk factor for late-onset AD [37,38], while some studies failed to find such an association [32,39].”
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“The expression of APOE4 leads to blood–brain barrier breakdown, the neuronal uptake of multiple blood-derived neurotoxic proteins, and microvascular and cerebral blood flow reduction via the activation of a proinflammatory CypA–nuclear factor-kB–matrixmetalloproteinase-9 pathway [34].”
BackgroundFRET-Protease-Coupled Peptidyl-Prolyl cis-trans Isomerase Assay
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“109 A greater appreciation for the potential roles of ApoE4 in health and disease may prove fruitful.”
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“APOE4 expression, in place of healthy APOE3, leads to enhanced basement membrane degradation by pericyte-secreted MMP-9 [51,52].”
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“CypA has been shown to directly bind with tau and studies have shown that it is elevated in ApoE4 astrocytes leading to CypA-NFkB-MMP-9-dependent blood–brain barrier (BBB) dysfunction [86].”
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Neurovascular imaging with QUTE-CE MRI in APOE4 rats reveals early vascular abnormalities
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“Literature suggests that BBB leakage is positively correlated to aging, cognitive decline and AD in APOE4 humans [51] BBB leakage was reported in 6-month-old ApoE4 mice of unknown gender [52], but it is hard to determine the implications for our study on female APOE4 rats.”
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“Since CypA contributes to a wide range of diseases including cancers [14], inflammation [15] as in the case of atherosclerosis [16], neurodegenerative diseases [17] like Alzheimer’s disease [17], and viral infections [18–20], it represents a valuable drug target [21].”
BackgroundDNA methylation biomarkers for cumulative lead exposures and cognitive impairment
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“However, it can mediate BBB dysfunction in the presence of APOE4, a major genetic risk factor for AD [8,9].”
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“Additionally, ApoE4 expression, but not ApoE3 and ApoE2, can promote vascular defects and impair blood– brain barrier integrity prior to neuronal dysfunction (Barisano et al., 2022; Bell et al., 2012; Jackson et al., 2022).”
BackgroundVascular hypothesis of Alzheimer’s disease: role of apoE and apoE receptors
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“Because apoE4 is known to damage blood-brain barrier (BBB) integrity and reduces small cerebral vessels [5], apoE is likely involved in the maintenance of cognitive function through regulating the function of cerebrovascular systems.”
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“The presence of apoE4 activates a pro-inflammatory signaling pathway in pericytes, including Cyclophilin A–nuclear factor-κB–matrix-metalloproteinase-9 (MMP9), leading to the destruction of the blood–brain barrier, with neuronal dysfunction [22].”
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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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