The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index.
Lack of Widespread BBB Disruption in Alzheimer’s Disease Models: Focus on Therapeutic Antibodies
Open accessAbstract
The blood-brain barrier (BBB) limits brain uptake of therapeutic antibodies. It is believed that the BBB is disrupted in Alzheimer's disease (AD), potentially increasing drug permeability de facto. Here we compared active versus passive brain uptake of systemically dosed antibodies (anti-transferrin receptor [TfR] bispecific versus control antibody) in mouse models of AD. We first confirmed BBB disruption in a mouse model of multiple sclerosis as a positive control. Importantly, we found that BBB permeability was vastly spared in mouse models of AD, including PS2-APP, Tau transgenics, and APOE4 knockin mice. Brain levels of TfR in mouse models or in human cases of AD resembled controls, suggesting target engagement of TfR bispecific is not limited. Furthermore, infarcts from human AD brain showed similar occurrences compared to age-matched controls. These results question the widely held view that the BBB is largely disrupted in AD, raising concern about assumptions of drug permeability in disease.
Overview
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
Verification
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?
The cited source says what the claim attributes to it.
In the citing paper
“Although some studies have shown that ApoE4 disrupts BBB integrity in non-APP mice, it was recently reported that non-APP ApoE4 knock-in mice do not have any widespread BBB disruption [27].”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [27]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 4,875
Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model
Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S.-M., Iwata, N., Saido, T. C., Maeda, J., Suhara, T., Trojanowski, J. Q., & Lee, V. M.-Y. (2007) · Neuron · doi:10.1016/j.neuron.2007.01.010 · Cited by 2,208
Blood-brain barrier breakdown in the aging human hippocampus
Montagne, A., Barnes, S. R., Sweeney, M. D., Halliday, M. R., Sagare, A. P., Zhao, Z., Toga, A. W., Jacobs, R. E., Liu, C. Y., Amezcua, L., et al. (2015) · Neuron · doi:10.1016/j.neuron.2014.12.032 · Cited by 2,102
Apolipoprotein 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 3×
“However, BBB impairments may exist in non-amyloid-depositing AD models such as APOE4 mice (Bell et al., 2012) or mutant human tau transgenic mice (Blair et al., 2015).”
BackgroundMethodBlood–brain barrier: Ageing and microvascular disease – systematic review and meta-analysis
Farrall, A. J., & Wardlaw, J. M. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.07.015 · Cited by 882
Toledo, J. B., Arnold, S. E., Raible, K., Brettschneider, J., Xie, S. X., Grossman, M., Monsell, S. E., Kukull, W. A., & Trojanowski, J. Q. (2013) · Brain · doi:10.1093/brain/awt188 · Cited by 849
Boosting Brain Uptake of a Therapeutic Antibody by Reducing Its Affinity for a Transcytosis Target
Yu, Y. J., Zhang, Y., Kenrick, M., Hoyte, K., Luk, W., Lu, Y., Atwal, J., Elliott, J. M., Prabhu, S., Watts, R. J., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002230 · Cited by 794
Self-citationBlood brain barrier: ageing and microvascular disease-systematic review and meta-analysis
Farrall, A., & Wardlaw, J. M. (2009) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2009.02.089 · Cited by 640
Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease
Erickson, M. A., & Banks, W. A. (2013) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2013.135 · Cited by 572
Tau filament formation in transgenic mice expressing P301L tau
Götz, J., Chen, F., Barmettler, R., & Nitsch, R. M. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m006531200 · Cited by 495
Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program
Beach, T. G., Adler, C. H., Sue, L. I., Serrano, G., Shill, H. A., Walker, D. G., Lue, L., Roher, A. E., Dugger, B. N., Maarouf, C., et al. (2015) · Neuropathology · doi:10.1111/neup.12189 · Cited by 460
Self-citationTransferrin receptor (TfR) trafficking determines brain uptake of TfR antibody affinity variants
Bien‐Ly, N., Yu, Y. J., Bumbaca, D., Elstrott, J., Boswell, C. A., Zhang, Y., Luk, W., Lu, Y., Dennis, M. S., Weimer, R. M., et al. (2014) · The Journal of Experimental Medicine · doi:10.1084/jem.20131660 · Cited by 356
Self-citationAddressing Safety Liabilities of TfR Bispecific Antibodies That Cross the Blood-Brain Barrier
Couch, J. A., Yu, Y. J., Zhang, Y., Tarrant, J. M., Fuji, R. N., Meilandt, W. J., Solanoy, H. O., Tong, R. K., Hoyte, K., Luk, W., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3005338 · Cited by 278
Self-citationA Therapeutic Antibody Targeting BACE1 Inhibits Amyloid-β Production in Vivo
Atwal, J. K., Chen, Y., Chiu, C., Mortensen, D. L., Meilandt, W. J., Liu, Y., Heise, C. E., Hoyte, K., Luk, W., Lu, Y., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002254 · Cited by 274
Self-citationBennett, J. L., Basivireddy, J., Kollar, A., Biron, K. E., Reickmann, P., Jefferies, W. A., & McQuaid, S. (2010) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2010.08.011 · Cited by 271
Terwel, D., Lasrado, R., Snauwaert, J., Vandeweert, E., Haesendonck, C. V., Borghgraef, P., & LEUVEN, F. V. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m409876200 · Cited by 267
Sporadic cerebral amyloid angiopathy: pathology, clinical implications, and possible pathomechanisms
Attems, J. (2005) · Acta Neuropathologica · doi:10.1007/s00401-005-1074-9 · Cited by 242
Developing Therapeutic Antibodies for Neurodegenerative Disease
Yu, Y. J., & Watts, R. J. (2013) · Neurotherapeutics · doi:10.1007/s13311-013-0187-4 · Cited by 231
Self-citationSt‐Amour, I., Paré, I., Alata, W., Coulombe, K., Goulet, C. R., Drouin‐Ouellet, J., Vandal, M., Soulet, D., Bazin, R., & Calon, F. (2013) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2013.160 · Cited by 194
Phares, T. W., Kean, R. B., Mikheeva, T., & Hooper, D. C. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.12.7666 · Cited by 193
Tau depletion prevents progressive blood-brain barrier damage in a mouse model of tauopathy
Blair, L. J., Frauen, H. D., Zhang, B., Nordhues, B. A., Bijan, S., Lin, Y.-C., Zamudio, F., Hernandez, L. D., Sabbagh, J. J., Selenica, M.-L. B., et al. (2015) · Acta Neuropathologica Communications · doi:10.1186/s40478-015-0186-2 · Cited by 193
Alata, W., Ye, Y., St‐Amour, I., Vandal, M., & Calon, F. (2014) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2014.172 · Cited by 164
Neurovascular function in Alzheimer's disease patients and experimental models
Nicolakakis, N., & Hamel, E. (2011) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2011.43 · Cited by 156
ApoE deficiency leads to a progressive age-dependent blood-brain barrier leakage
Hafezi-Moghadam, A., Thomas, K. L., & Wagner, D. D. (2007) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00563.2005 · Cited by 149
Han, B. H., Zhou, M.-L., Abousaleh, F., Brendza, R. P., Dietrich, H. H., Koenigsknecht-Talboo, J., Cirrito, J. R., Milner, E., Holtzman, D. M., & Zipfel, G. J. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4686-08.2008 · Cited by 138
Takeda, S., Sato, N., Ikimura, K., Nishino, H., Rakugi, H., & Morishita, R. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.02.010 · Cited by 135 · cited 1×
“An additional group of 5-month-old WT mice were LPS-injected 6 hr before trace-dosing to serve as a model with reported BBB disruption (Takeda et al., 2013).”
MethodMaier, F. C., Wehrl, H. F., Schmid, A. M., Mannheim, J. G., Wiehr, S., Lerdkrai, C., Calaminus, C., Stahlschmidt, A., Ye, L., Burnet, M. W. M., et al. (2014) · Nature Medicine · doi:10.1038/nm.3734 · Cited by 122
Phosphorylation of Tau at S422 is enhanced by Aβ in TauPS2APP triple transgenic mice
Grueninger, F., Bohrmann, B., Czech, C., Ballard, T. M., Frey, J. R., Weidensteiner, C., von Kienlin, M., & Ozmen, L. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.09.004 · Cited by 117
Chizzonite, R., Truitt, T., Podlaski, F., Wolitzky, A. G., Quinn, P. M., Nunes, P., STERN, A. S., & Gately, M. K. (1991) · The Journal of Immunology · doi:10.4049/jimmunol.147.5.1548 · Cited by 112
Schlageter, N. L., Carson, R. E., & Rapoport, S. I. (1987) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.1987.1 · Cited by 107
Ozmen, L., Albientz, A., Czech, C., & Jacobsen, H. (2008) · Neurodegenerative Diseases · doi:10.1159/000170884 · Cited by 99
Bridges, L., Andoh, J., Lawrence, A. J., Khoong, C. H. L., Poon, W. W., Esiri, M. M., Markus, H. S., & Hainsworth, A. H. (2014) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0000000000000124 · Cited by 98
Hanyu, H., Sato, T., Hirao, K., Kanetaka, H., Iwamoto, T., & Koizumi, K. (2009) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2009.10.022 · Cited by 95
Do, T. M., Alata, W., Dodacki, A., Traversy, M.-T., Chacun, H., Pradier, L., Scherrmann, J.-M., Farinotti, R., Calon, F., & Bourasset, F. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.02.010 · Cited by 77
Bateman, G. A., Levi, C. R., Schofield, P., Wang, Y., & Lovett, E. C. (2006) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2005.04.017 · Cited by 64
Boswell, C. A., Bumbaca, D., Fielder, P. J., & Khawli, L. A. (2012) · The AAPS Journal · doi:10.1208/s12248-012-9374-1 · Cited by 62
Self-citationA Therapeutic Antibody Targeting Bace1 Inhibits Amyloid-beta Production in Vivo
Atwal, J. K., Chen, Y., Chiu, C. W., Mortensen, D. L., Meilandt, W. J., liu, Y., Heise, C., Hoyte, K., Luk, W., Lu, Y., et al. (2013) · OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) · Cited by 56
Self-citationKallop, D. Y., Meilandt, W. J., Gogineni, A., Easley-Neal, C., Wu, T., Jubb, A. M., Yaylaoglu, M., Shamloo, M., Tessier-Lavigne, M., Scearce-Levie, K., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.4963-13.2014 · Cited by 54
Alzheimer's disease with and without cerebral infarcts
del Ser, T., Hachinski, V., Merskey, H., & Muñoz, D. G. (2004) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2004.08.016 · Cited by 53
The significance of small cerebral bleeds in neurodegenerative dementia syndromes.
Reuck, J. L. D. (2012) · Europe PMC (PubMed Central) · Cited by 20
Cited by
Sorted by citations
Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C., & Bu, G. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0228-7 · Cited by 1,425
Current Strategies for Brain Drug Delivery
Dong, X. (2018) · Theranostics · doi:10.7150/thno.21254 · Cited by 954
“measured levels of transferrin receptor in brain samples from both AD animal models and AD patients, and did not observe any decreases [48].”
ResultBlood-brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound
Lipsman, N., Meng, Y., Bethune, A. J., Huang, Y., Lam, B., Masellis, M., Herrmann, N., Heyn, C., Aubert, I., Boutet, A., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04529-6 · Cited by 950
The blood–brain barrier in health and disease: Important unanswered questions
Profaci, C. P., Munji, R. N., Pulido, R. S., & Daneman, R. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20190062 · Cited by 811
Alzheimer’s disease: A matter of blood–brain barrier dysfunction?
Montagne, A., Zhao, Z., & Zlokovic, B. V. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20171406 · Cited by 672
Metadata
- Authors
- Bien-Ly, N., Boswell, C. A., Jeet, S., Beach, T. G., Hoyte, K., Luk, W., Shihadeh, V., Ulufatu, S., Foreman, O., Lu, Y., DeVoss, J., van der Brug, M., & Watts, R. J.
- Affiliations
- Genentech (US)
- Banner Sun Health Research Institute (US)
- Corresponding author
- van der Brug, Marcel
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 88
- Issue
- 2
- Pages
- 289-297
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2158547909
- Cited by
- 198
- References
- 40
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 12 · 2023: 17 · 2022: 15 · 2021: 24 · 2020: 16 · 2019: 25 · 2018: 18 · 2017: 25 · 2016: 19 · 2015: 4
- FWCI
- 11.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- blood-brain barrier, Alzheimer's disease, therapeutic antibodies, transferrin receptor, bispecific antibodies, blood-brain barrier permeability, APP transgenic mice, tau transgenic mice, infarction, drug permeability
- MeSH terms
- Alzheimer Disease, Animals, Antibodies, Blood-Brain Barrier, Disease Models, Animal, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Recombinant Fusion Proteins, Mice, Knockout, Mice, Single-Chain Antibodies
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
