Passive immunotherapy targeting amyloid-β reduces cerebral amyloid angiopathy and improves vascular reactivity
Abstract
Prominent cerebral amyloid angiopathy is often observed in the brains of elderly individuals and is almost universally found in patients with Alzheimer's disease. Cerebral amyloid angiopathy is characterized by accumulation of the shorter amyloid-β isoform(s) (predominantly amyloid-β40) in the walls of leptomeningeal and cortical arterioles and is likely a contributory factor to vascular dysfunction leading to stroke and dementia in the elderly. We used transgenic mice with prominent cerebral amyloid angiopathy to investigate the ability of ponezumab, an anti-amyloid-β40 selective antibody, to attenuate amyloid-β accrual in cerebral vessels and to acutely restore vascular reactivity. Chronic administration of ponezumab to transgenic mice led to a significant reduction in amyloid and amyloid-β accumulation both in leptomeningeal and brain vessels when measured by intravital multiphoton imaging and immunohistochemistry. By enriching for cerebral vascular elements, we also measured a significant reduction in the levels of soluble amyloid-β biochemically. We hypothesized that the reduction in vascular amyloid-β40 after ponezumab administration may reflect the ability of ponezumab to mobilize an interstitial fluid pool of amyloid-β40 in brain. Acutely, ponezumab triggered a significant and transient increase in interstitial fluid amyloid-β40 levels in old plaque-bearing transgenic mice but not in young animals. We also measured a beneficial effect on vascular reactivity following…
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Aβ immunotherapy can ameliorate VAβ burden and improve compromised vascular reactivity.
“Aβ immunotherapy can ameliorate VAβ burden and improve compromised vascular reactivity [12, 21, 63], but it is well known to escalate incidence of brain microhemorrhages [21, 26].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [63]
Cites
Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease
Salloway, S., Sperling, R., Fox, N. C., Blennow, K., Klunk, W., Raskind, M., Sabbagh, M., Honig, L. S., Porsteinsson, A. P., Ferris, S., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1304839 · Cited by 1,960 · see citing works
Alzheimer disease and cerebrovascular pathology: an update
Jellinger, K. A. (2002) · Journal of Neural Transmission · doi:10.1007/s007020200068 · Cited by 680 · see citing works
Sperling, R., Salloway, S., Brooks, D. J., Tampieri, D., Barakos, J., Fox, N. C., Raskind, M., Sabbagh, M., Honig, L. S., Porsteinsson, A. P., et al. (2012) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70015-7 · Cited by 512 · see citing works
Herzig, M. C., Winkler, D. T., Burgermeister, P., Pfeifer, M., Kohler, E., Schmidt, S. D., Danner, S., Abramowski, D., Stürchler-Pierrat, C., Bürki, K., et al. (2004) · Nature Neuroscience · doi:10.1038/nn1302 · Cited by 391 · see citing works
Cerebrovascular lesions induce transient -amyloid deposition
Garcia-Alloza, M., Gregory, J., Kuchibhotla, K. V., Fine, S., Wei, Y., Ayata, C., Frosch, M. P., Greenberg, S. M., & Bacskai, B. J. (2011) · Brain · doi:10.1093/brain/awr300 · Cited by 187 · see citing works
Ly, J. V., Donnan, G. A., Villemagne, V. L., Zavala, J. A., Ma, H., O'Keefe, G., Gong, S. J., Gunawan, R. M., Saunder, T., Ackerman, U., et al. (2010) · Neurology · doi:10.1212/wnl.0b013e3181cef7e3 · Cited by 157 · see citing works
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 · see citing works
Self-citationParis, D., Humphrey, J., Quadros, A., Patel, N., Crescentini, R., Crawford, F., & Mullan, M. (2003) · Neurological Research · doi:10.1179/016164103101201940 · Cited by 127 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The neuropathological diagnosis of Alzheimer's disease
DeTure, M. A., & Dickson, D. W. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0333-5 · Cited by 3,329 · see citing works
“Interestingly, immunization strategies targeting Aβ peptides may be useful in alleviating amyloid plaque burden, while shifting amyloid into CAA, sometimes associated with inflammation and hemorrhage [51, 52].”
BackgroundEmerging concepts in sporadic cerebral amyloid angiopathy
Charidimou, A., Boulouis, G., Gurol, M. E., Ayata, C., Bacskai, B. J., Frosch, M. P., Viswanathan, A., & Greenberg, S. M. (2017) · Brain · doi:10.1093/brain/awx047 · Cited by 555 · see citing works
Xiong, M., Jiang, H., Serrano, J. R., Gonzales, E. R., Wang, C., Gratuze, M., Hoyle, R., Bien-Ly, N., Silverman, A. P., Sullivan, P. M., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abd7522 · Cited by 179 · see citing works
Self-citationLacosta, A.-M., Pascual-Lucas, M., Pesini, P., Casabona, D., Pérez-Grijalba, V., Marcos-Campos, I., Sarasa, L., Canudas, J., Badi, H., Monleón, I., et al. (2018) · Alzheimer's Research & Therapy · doi:10.1186/s13195-018-0340-8 · Cited by 111 · see citing works
Saito, S., Yamamoto, Y., Maki, T., Hattori, Y., Ito, H., Mizuno, K., Harada-Shiba, M., Kalaria, R. N., Fukushima, M., Takahashi, R., et al. (2017) · Acta Neuropathologica Communications · doi:10.1186/s40478-017-0429-5 · Cited by 110 · see citing works
Cerebrovascular pathology in Down syndrome and Alzheimer disease
Head, E., Phelan, M. J., Doran, E., Kim, R. C., Poon, W. W., Schmitt, F. A., & Lott, I. T. (2017) · Acta Neuropathologica Communications · doi:10.1186/s40478-017-0499-4 · Cited by 105 · see citing works
Pankiewicz, J. E., Baquero-Buitrago, J., Sanchez, S., Lopez-Contreras, J., Kim, J., Sullivan, P. M., Holtzman, D. M., & Sadowski, M. J. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0156-1 · Cited by 34 · see citing works
“Aβ immunotherapy can ameliorate VAβ burden and improve compromised vascular reactivity [12, 21, 63], but it is well known to escalate incidence of brain microhemorrhages [21, 26].”
BackgroundGJ-4 alleviates Aβ25-35-induced memory dysfunction in mice through protecting the neurovascular unit
Zhang, Z., Liu, H., Zhao, Z., Zang, C., Ju, C., Li, F., Wang, L., Yang, H., Bao, X., Yu, Y., et al. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110131 · Cited by 19 · see citing works
- Authors
- Bales, K. R., O’Neill, S. M., Pozdnyakov, N., Pan, F., Caouette, D., Pi, Y., Wood, K. M., Volfson, D., Cirrito, J. R., Han, B.-H., Johnson, A. W., Zipfel, G. J., & Samad, T. A.
- Affiliations
- Pfizer (United States) (US)
- 1 Pfizer Neuroscience and Pain Research Unit, 610 Main Street, Cambridge MA 02139, USA
- Washington University in St. Louis (US)
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-10-22
- Volume
- 139
- Issue
- 2
- Pages
- 563-577
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2231734233
- Cited by
- 68
- References
- 8
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 3 · 2023: 7 · 2022: 8 · 2021: 8 · 2020: 6 · 2019: 8 · 2018: 3 · 2017: 11 · 2016: 2
- FWCI
- 3.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- cerebral amyloid angiopathy, Aβ40, passive immunotherapy, anti-amyloid beta antibodies, vascular reactivity, leptomeningeal vessels, Alzheimer's disease, transgenic mice, vascular dysfunction
- MeSH terms
- Animals, Cerebrovascular Circulation, Endothelium, Vascular, Female, Immunization, Passive, Male, Mice, Transgenic, Amyloid beta-Peptides, Cerebral Amyloid Angiopathy, Mice, Plaque, Amyloid, Antibodies, Monoclonal, Humanized
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
