Vascular ApoE4 impairs behavior by modulating gliovascular function
Open accessAbstract
The ε4 allele of the apolipoprotein E gene (APOE4) is a strong genetic risk factor for Alzheimer's disease (AD) and multiple vascular conditions. ApoE is abundantly expressed in multiple brain cell types, including astrocytes, microglia, and vascular mural cells (VMCs). Here, we show that VMC-specific expression of apoE4 in mice impairs behavior and cerebrovascular function. Expression of either apoE3 or apoE4 in VMCs was sufficient to rescue the hypercholesterolemia and atherosclerosis phenotypes seen in Apoe knockout mice. Intriguingly, vascular expression of apoE4, but not apoE3, reduced arteriole blood flow, impaired spatial learning, and increased anxiety-like phenotypes. Single-cell RNA sequencing of vascular and glial cells revealed that apoE4 in VMCs was associated with astrocyte activation, while apoE3 was linked to angiogenic signature in pericytes. Together, our data support cell-autonomous effects of vascular apoE on brain homeostasis in an isoform-dependent manner, suggesting a critical contribution of vascular apoE to AD pathogenesis.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Specific expression of apoE4, but not apoE3, in vascular mural cells impairs cerebrovascular function and spatial learning in mice.
“specific expression of apoE4, but not apoE3, in vascular mural cells impairs cerebrovascular function and spatial learning in mice”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Yamazaki et al 2021
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Gorelick, P. B., Scuteri, A., Black, S. E., DeCarli, C., Greenberg, S. M., Iadecola, C., Launer, L. J., Laurent, S., Lopez, O. L., Nyenhuis, D., et al. (2011) · Stroke · doi:10.1161/str.0b013e3182299496 · Cited by 3,811 · see citing works
A molecular atlas of cell types and zonation in the brain vasculature
Vanlandewijck, M., He, L., Mäe, M. A., Andrae, J., Ando, K., Del Gaudio, F., Nahar, K., Lebouvier, T., Laviña, B., Gouveia, L., et al. (2018) · Nature · doi:10.1038/nature25739 · Cited by 2,074 · cited 4× · see citing works
“Annotation of Cell Clusters for Specific Cell Type—The annotation of each cluster was manually performed using the datasets for murine cell taxonomy (Saunders et al., 2018; Vanlandewijck et al., 2018).”
BackgroundMethodInfluentialMolecular diversity and specializations among the cells of the adult mouse brain
Saunders, A., Macosko, E. Z., Wysoker, A., Goldman, M., Krienen, F. M., de Rivera, H., Bien, E., Baum, M., Bortolin, L., Wang, S., et al. (2018) · Cell · doi:10.1016/j.cell.2018.07.028 · Cited by 1,847 · cited 1× · see citing works
“Annotation of Cell Clusters for Specific Cell Type—The annotation of each cluster was manually performed using the datasets for murine cell taxonomy (Saunders et al., 2018; Vanlandewijck et al., 2018).”
MethodApolipoprotein E controls cerebrovascular integrity via cyclophilin A
Bell, R. D., Winkler, E. A., Singh, I., Sagare, A. P., Deane, R., Wu, Z., Holtzman, D. M., Betsholtz, C., Armulik, A., Sallstrom, J., et al. (2012) · Nature · doi:10.1038/nature11087 · Cited by 1,293 · cited 1× · see citing works
“, 1995), BBB dysfunction (Bell et al., 2012; Fullerton et al., 2001), and hypercholesterolemia are reported in the absence of murine apoE.”
BackgroundSullivan, P. M., Mezdour, H., Aratani, Y., Knouff, C., Najib, J., Reddick, R. L., Quarfordt, S. H., & Maeda, N. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.29.17972 · Cited by 575 · see citing works
Toth, P., Tarantini, S., Csiszar, A., & Ungvari, Z. (2017) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00581.2016 · Cited by 522 · see citing works
Vascular Cell Senescence Contributes to Blood–Brain Barrier Breakdown
Yamazaki, Y., Baker, D. J., Tachibana, M., Liu, C.-C., van Deursen, J. M., Brott, T. G., Bu, G., & Kanekiyo, T. (2016) · Stroke · doi:10.1161/strokeaha.115.010835 · Cited by 263 · see citing works
Self-citationGetz, G. S., & Reardon, C. A. (2016) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.116.306874 · Cited by 198 · see citing works
APOE ε2 is associated with increased tau pathology in primary tauopathy
Zhao, N., Liu, C.-C., Van Ingelgom, A. J., Linares, C., Kurti, A., Knight, J. A., Heckman, M. G., Diehl, N. N., Shinohara, M., Martens, Y. A., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06783-0 · Cited by 139 · cited 2× · see citing works
“Cognitive and Behavioral Tests—Contextual and cued fear conditioning (CFC), Morris water maze (MWM), open-field assay (OFA) and elevated plus maze (EPM) tests were performed as described (Kang et al., 2018; Sakae et al., 2016; Zhao et al., 2018).”
MethodSelf-citationYamazaki, Y., Shinohara, M., Yamazaki, A., Ren, Y., Asmann, Y. W., Kanekiyo, T., & Bu, G. (2020) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.119.313169 · Cited by 89 · see citing works
Self-citationBehavioral and transcriptomic analysis of Trem2-null mice: not all knockout mice are created equal
Kang, S. S., Kurti, A., Baker, K. E., Liu, C.-C., Colonna, M., Ulrich, J. D., Holtzman, D. M., Bu, G., & Fryer, J. D. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddx366 · Cited by 62 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 43
- Alata W, Ye Y, St-Amour I, Vandal M, and Calon F (2015). Human apolipoprotein E varepsilon4 expression impairs cerebral vascularization and blood-brain barrier function in mice. J Cereb Blood Flow Metab 35, 86– 94. 25335802 PMC4296574
- Bellosta S, Mahley RW, Sanan DA, Murata J, Newland DL, Taylor JM, and Pitas RE (1995). Macrophage-specific expression of human apolipoprotein E reduces atherosclerosis in hypercholesterolemic apolipoprotein E-null mice. J Clin Invest 96, 2170– 2179. 7593602 PMC185866
- Boucher P, Gotthardt M, Li WP, Anderson RG, and Herz J (2003). LRP: role in vascular wall integrity and protection from atherosclerosis. Science 300, 329– 332. 12690199
- Caselli RJ, Dueck AC, Osborne D, Sabbagh MN, Connor DJ, Ahern GL, Baxter LC, Rapcsak SZ, Shi J, Woodruff BK, (2009). Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect. N Engl J Med 361, 255– 263. 19605830 PMC2928998
- Casey CS, Atagi Y, Yamazaki Y, Shinohara M, Tachibana M, Fu Y, Bu G, and Kanekiyo T (2015). Apolipoprotein E Inhibits Cerebrovascular Pericyte Mobility through a RhoA Protein-mediated Pathway. J Biol Chem 290, 14208– 14217. 25903128 PMC4447989
- Chistiakov DA, Myasoedova VA, Revin VV, Orekhov AN, and Bobryshev YV (2017). The phenomenon of atherosclerosis reversal and regression: Lessons from animal models. Exp Mol Pathol 102, 138– 145. 28108216
- Cruz Hernandez JC, Bracko O, Kersbergen CJ, Muse V, Haft-Javaherian M, Berg M, Park L, Vinarcsik LK, Ivasyk I, Rivera DA, (2019). Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models. Nat Neurosci 22, 413– 420. 30742116 PMC6508667
- Delenclos M, Faroqi AH, Yue M, Kurti A, Castanedes-Casey M, Rousseau L, Phillips V, Dickson DW, Fryer JD, and McLean PJ (2017). Neonatal AAV delivery of alpha-synuclein induces pathology in the adult mouse brain. Acta Neuropathol Commun 5, 51. 28645308 PMC5481919
- Di Battista AM, Heinsinger NM, and Rebeck GW (2016). Alzheimer’s Disease Genetic Risk Factor APOE-epsilon4 Also Affects Normal Brain Function. Curr Alzheimer Res 13, 1200– 1207. 27033053 PMC5839141
- Drew PJ, Blinder P, Cauwenberghs G, Shih AY, and Kleinfeld D (2010). Rapid determination of particle velocity from space-time images using the Radon transform. J Comput Neurosci 29, 5– 11. 19459038 PMC4962871
- Fullerton SM, Shirman GA, Strittmatter WJ, and Matthew WD (2001). Impairment of the blood-nerve and blood-brain barriers in apolipoprotein e knockout mice. Exp Neurol 169, 13– 22. 11312553
- Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M, Combarros O, Bullido MJ, Engelborghs S, De Deyn P, Berr C, (2011). APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry 16, 903– 907. 21556001 PMC3162068
- Halliday MR, Pomara N, Sagare AP, Mack WJ, Frangione B, and Zlokovic BV (2013). Relationship between cyclophilin a levels and matrix metalloproteinase 9 activity in cerebrospinal fluid of cognitively normal apolipoprotein e4 carriers and blood-brain barrier breakdown. JAMA Neurol 70, 1198– 1200. 24030206 PMC4047029
- Kanekiyo T, Liu CC, Shinohara M, Li J, and Bu G (2012). LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer’s amyloid-beta. J Neurosci 32, 16458– 16465. 23152628 PMC3508699
- Knouff C, Hinsdale ME, Mezdour H, Altenburg MK, Watanabe M, Quarfordt SH, Sullivan PM, and Maeda N (1999). Apo E structure determines VLDL clearance and atherosclerosis risk in mice. J Clin Invest 103, 1579– 1586. 10359567 PMC408371
- Liu CC, Kanekiyo T, Xu H, and Bu G (2013). Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9, 106– 118. 23296339 PMC3726719
- Liu CC, Zhao N, Fu Y, Wang N, Linares C, Tsai CW, and Bu G (2017). ApoE4 Accelerates Early Seeding of Amyloid Pathology. Neuron 96, 1024– 1032 e1023. 29216449 PMC5948105
- Luo X, Jiaerken Y, Yu X, Huang P, Qiu T, Jia Y, Li K, Xu X, Shen Z, Guan X, (2017). Associations between APOE genotype and cerebral small-vessel disease: a longitudinal study. Oncotarget 8, 44477– 44489. 28574812 PMC5546495
- Mahley RW (2016). Central Nervous System Lipoproteins: ApoE and Regulation of Cholesterol Metabolism. Arterioscler Thromb Vasc Biol 36, 1305– 1315. 27174096 PMC4942259
- Masliah E, Mallory M, Ge N, Alford M, Veinbergs I, and Roses AD (1995). Neurodegeneration in the central nervous system of apoE-deficient mice. Exp Neurol 136, 107– 122. 7498401
- Najm R, Jones EA, and Huang Y (2019). Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease. Mol Neurodegener 14, 24. 31186040 PMC6558779
- Pelligrino DA, Vetri F, and Xu HL (2011). Purinergic mechanisms in gliovascular coupling. Semin Cell Dev Biol 22, 229– 236. 21329762 PMC3070818
- Rasmussen KL, Tybjaerg-Hansen A, Nordestgaard BG, and Frikke-Schmidt R (2018). Absolute 10-year risk of dementia by age, sex and APOE genotype: a population-based cohort study. CMAJ 190, E1033– E1041. 30181149 PMC6148649
- Rodriguez GA, Burns MP, Weeber EJ, and Rebeck GW (2013). Young APOE4 targeted replacement mice exhibit poor spatial learning and memory, with reduced dendritic spine density in the medial entorhinal cortex. Learn Mem 20, 256– 266. 23592036 PMC3630489
- Rogers JT, Liu CC, Zhao N, Wang J, Putzke T, Yang L, Shinohara M, Fryer JD, Kanekiyo T, and Bu G (2017). Subacute ibuprofen treatment rescues the synaptic and cognitive deficits in advanced-aged mice. Neurobiol Aging 53, 112– 121. 28254590 PMC5385269
- Rojas S, Brugulat-Serrat A, Bargallo N, Minguillon C, Tucholka A, Falcon C, Carvalho A, Moran S, Esteller M, Gramunt N, (2018). Higher prevalence of cerebral white matter hyperintensities in homozygous APOE-varepsilon4 allele carriers aged 45–75: Results from the ALFA study. J Cereb Blood Flow Metab 38, 250– 261. 28492093 PMC5951016
- Sakae N, Liu CC, Shinohara M, Frisch-Daiello J, Ma L, Yamazaki Y, Tachibana M, Younkin L, Kurti A, Carrasquillo MM, (2016). ABCA7 Deficiency Accelerates Amyloid-beta Generation and Alzheimer’s Neuronal Pathology. J Neurosci 36, 3848– 3859. 27030769 PMC4812140
- Salomon-Zimri S, Boehm-Cagan A, Liraz O, and Michaelson DM (2014). Hippocampus-related cognitive impairments in young apoE4 targeted replacement mice. Neurodegener Dis 13, 86– 92. 24080852
- Satija R, Farrell JA, Gennert D, Schier AF, and Regev A (2015). Spatial reconstruction of single-cell gene expression data. Nat Biotechnol 33, 495– 502. 25867923 PMC4430369
- Schilling S, DeStefano AL, Sachdev PS, Choi SH, Mather KA, DeCarli CD, Wen W, Hogh P, Raz N, Au R, (2013). APOE genotype and MRI markers of cerebrovascular disease: systematic review and meta-analysis. Neurology 81, 292– 300. 23858411 PMC3770168
- Shen Z, Lu Z, Chhatbar PY, O’Herron P, and Kara P (2012). An artery-specific fluorescent dye for studying neurovascular coupling. Nat Methods 9, 273– 276. 22266543 PMC3392962
- Shinohara M, Kanekiyo T, Yang L, Linthicum D, Shinohara M, Fu Y, Price L, Frisch-Daiello JL, Han X, Fryer JD, and Bu G (2016). APOE2 eases cognitive decline during Aging: Clinical and preclinical evaluations. Ann Neurol 79, 758– 774. 26933942 PMC5010530
- Siegel JA, Haley GE, and Raber J (2012). Apolipoprotein E isoform-dependent effects on anxiety and cognition in female TR mice. Neurobiol Aging 33, 345– 358. 20400205 PMC2935518
- Sudre CH, Cardoso MJ, Frost C, Barnes J, Barkhof F, Fox N, Ourselin S, and Alzheimer’s Disease Neuroimaging I (2017). APOE epsilon4 status is associated with white matter hyperintensities volume accumulation rate independent of AD diagnosis. Neurobiol Aging 53, 67– 75. 28235680
- Sun JH, Tan L, Wang HF, Tan MS, Tan L, Li JQ, Xu W, Zhu XC, Jiang T, and Yu JT (2015). Genetics of Vascular Dementia: Systematic Review and Meta-Analysis. J Alzheimers Dis 46, 611– 629. 25835425
- Tai LM, Thomas R, Marottoli FM, Koster KP, Kanekiyo T, Morris AW, and Bu G (2016). The role of APOE in cerebrovascular dysfunction. Acta Neuropathol 131, 709– 723. 26884068 PMC4837016
- Thambisetty M, Beason-Held L, An Y, Kraut MA, and Resnick SM (2010). APOE epsilon4 genotype and longitudinal changes in cerebral blood flow in normal aging. Arch Neurol 67, 93– 98. 20065135 PMC2856443
- Thorngate FE, Rudel LL, Walzem RL, and Williams DL (2000). Low levels of extrahepatic nonmacrophage ApoE inhibit atherosclerosis without correcting hypercholesterolemia in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 20, 1939– 1945. 10938015
- Vemuri P, Lesnick TG, Przybelski SA, Knopman DS, Preboske GM, Kantarci K, Raman MR, Machulda MM, Mielke MM, Lowe VJ, (2015). Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly. Brain 138, 761– 771. 25595145 PMC4339775
- Xu Q, Bernardo A, Walker D, Kanegawa T, Mahley RW, and Huang Y (2006). Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J Neurosci 26, 4985– 4994. 16687490 PMC6674234
- Yamazaki Y, Shinohara M, Shinohara M, Yamazaki A, Murray ME, Liesinger AM, Heckman MG, Lesser ER, Parisi JE, Petersen RC, (2019a). Selective loss of cortical endothelial tight junction proteins during Alzheimer’s disease progression. Brain 142, 1077– 1092. 30770921 PMC6439325
- Yamazaki Y, Zhao N, Caulfield TR, Liu CC, and Bu G (2019b). Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol 15, 501– 518. 31367008 PMC7055192
- Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, Benner C, and Chanda SK (2019). Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 10, 1523. 30944313 PMC6447622
Cited by
Sorted by citations
ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
Raulin, A.-C., Doss, S. V., Trottier, Z. A., Ikezu, T. C., Bu, G., & Liu, C.-C. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00574-4 · Cited by 756 · see citing works
Self-citationApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease
Li, Y., Macyczko, J. R., Liu, C.-C., & Bu, G. (2022) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2022.03.011 · Cited by 61 · see citing works
Self-citationZhao, J., Ikezu, T. C., Lu, W., Macyczko, J. R., Li, Y., Lewis-Tuffin, L. J., Martens, Y. A., Ren, Y., Zhu, Y., Asmann, Y. W., et al. (2023) · Stem Cell Research & Therapy · doi:10.1186/s13287-023-03444-y · Cited by 25 · see citing works
Self-citationApoE expression across the CNS: Who, What, Where, When, and How (much)?
Nolt, G. L., Lucido, C. C., Smith, L. M., & Johnson, L. A. (2026) · Molecular Neurodegeneration Advances · doi:10.1186/s44477-026-00028-x · Cited by 2 · see citing works
- Authors
- Yamazaki, Y., Liu, C.-C., Yamazaki, A., Shue, F., Martens, Y. A., Chen, Y., Qiao, W., Kurti, A., Oue, H., Ren, Y., Li, Y., Aikawa, T., Cherukuri, Y., Fryer, J. D., Asmann, Y. W., Kim, B. Y. S., Kanekiyo, T., & Bu, G.
- Affiliations
- Mayo Clinic (US)
- Mayo Clinic in Arizona (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Bu, Guojun
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2021-02
- Volume
- 109
- Issue
- 3
- Pages
- 438-447.e6
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC7864888
- OpenAlex
- W3111488141
- Cited by
- 71
- References
- 11
- Citations by year
- 2026: 13 · 2025: 9 · 2024: 15 · 2023: 16 · 2022: 13 · 2021: 5
- FWCI
- 4.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- apolipoprotein E, APOE ε4, APOE3, vascular mural cells, cerebrovascular function, Alzheimer's disease, hypercholesterolemia, atherosclerosis, spatial learning, anxiety-like behavior, astrocyte activation, pericytes, angiogenesis
- MeSH terms
- Animals, Arterioles, Astrocytes, Brain, Gliosis, Mice, Transgenic, Mice, Apolipoprotein E3, Apolipoprotein E4
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 ›
Are you an author, or do you see a problem with this page? Request a review
