Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models
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Abstract
Cerebral blood flow (CBF) reductions in Alzheimer's disease patients and related mouse models have been recognized for decades, but the underlying mechanisms and resulting consequences for Alzheimer's disease pathogenesis remain poorly understood. In APP/PS1 and 5xFAD mice we found that an increased number of cortical capillaries had stalled blood flow as compared to in wild-type animals, largely due to neutrophils that had adhered in capillary segments and blocked blood flow. Administration of antibodies against the neutrophil marker Ly6G reduced the number of stalled capillaries, leading to both an immediate increase in CBF and rapidly improved performance in spatial and working memory tasks. This study identified a previously uncharacterized cellular mechanism that explains the majority of the CBF reduction seen in two mouse models of Alzheimer's disease and demonstrated that improving CBF rapidly enhanced short-term memory function. Restoring cerebral perfusion by preventing neutrophil adhesion may provide a strategy for improving cognition in Alzheimer's disease patients.
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Neutrophil-block of 2% of capillaries was predicted to reduce blood flow by only 5%.
“neutrophil-block of 2% of capillaries, as observed, was predicted to reduce blood flow by only 5% (38).”
From Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes (2019) · cites this paper as [38]
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- Authors
- Cruz Hernández, J. C., Bracko, O., Kersbergen, C. J., Muse, V., Haft-Javaherian, M., Berg, M., Park, L., Vinarcsik, L. K., Ivasyk, I., Rivera, D. A., Kang, Y., Cortes-Canteli, M., Peyrounette, M., Doyeux, V., Smith, A., Zhou, J., Otte, G., Beverly, J. D., Davenport, E., Davit, Y., Lin, C. P., Strickland, S., Iadecola, C., Lorthois, S., Nishimura, N., & Schaffer, C. B.
- Affiliations
- Cornell University (US)
- Centre National de la Recherche Scientifique (FR)
- Harvard University (US)
- Rockefeller University (US)
- Corresponding author
- Nishimura, Nozomi
- Schaffer, Chris B.
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2019-02-11
- Volume
- 22
- Issue
- 3
- Pages
- 413-420
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC6508667
- OpenAlex
- W2911407981
- Cited by
- 508
- References
- 66
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- 2026: 53 · 2025: 73 · 2024: 74 · 2023: 75 · 2022: 79 · 2021: 66 · 2020: 53 · 2019: 33
- FWCI
- 39.59
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Open Archive Toulouse Archive Ouverte (University of Toulouse) (acceptedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Science Foundation
- Alzheimer's Drug Discovery Foundation
- L'Oreal USA
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (AG049952)
- National Institute on Aging (RF1AG049952, F32AG031620, R01AG049952)
- National Institute of Neurological Disorders and Stroke (R01NS108472, R01NS037853, R01NS097805)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- Alzheimer's disease, neutrophil adhesion, cerebral blood flow, APP/PS1 mice, 5xFAD mice, Ly6G, neutrophil depletion, memory impairment, spatial memory, working memory, cerebral perfusion
- MeSH terms
- Alzheimer Disease, Animals, Antibodies, Antigens, Ly, Brain, Capillaries, Disease Models, Animal, Female, Male, Memory, Mice, Inbred C57BL, Mice, Transgenic, Models, Neurological, Neutrophils, Peptide Fragments, Amyloid beta-Peptides
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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