Lack of Widespread BBB Disruption in Alzheimer’s Disease Models: Focus on Therapeutic Antibodies
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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.
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Some studies have shown that ApoE4 disrupts BBB integrity in non-APP mice, but non-APP ApoE4 knock-in mice do not have any widespread BBB disruption.
“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]
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Neuropathology of White Matter Lesions, Blood–Brain Barrier Dysfunction, and Dementia
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Vulnerability of the Hippocampus to Insults: Links to Blood–Brain Barrier Dysfunction
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Vascular and Neurogenic Rejuvenation in Aging Mice by Modulation of ASM
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Water-exchange MRI detects subtle blood-brain barrier breakdown in Alzheimer's disease rats
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Safety and Efficacy of Scanning Ultrasound Treatment of Aged APP23 Mice
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Metabolic Syndrome and the Cellular Phase of Alzheimer's Disease
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Molecular Insight into the Therapeutic Promise of TargetingAPOE4for Alzheimer’s Disease
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Pulse Pressure: An Emerging Therapeutic Target for Dementia
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Therapeutic antibodies – natural and pathological barriers and strategies to overcome them
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- 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)
- 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
- Health Sciences › Medicine › Physiology › 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
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