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Immunotherapy Reduces Vascular Amyloid- in PDAPP Mice
Open accessAbstract
In addition to parenchymal amyloid-beta (Abeta) plaques, Alzheimer's disease (AD) is characterized by Abeta in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in the majority of patients. Recent studies investigating vascular Abeta (VAbeta) in amyloid precursor protein transgenic mice have suggested that passive immunization with anti-Abeta antibodies may clear parenchymal amyloid but increase VAbeta and the incidence of microhemorrhage. However, the influences of antibody specificity and exposure levels on VAbeta and microhemorrhage rates have not been well established, nor has any clear causal relationship been identified. This report examines the effects of chronic, passive immunization on VAbeta and microhemorrhage in PDAPP mice by comparing antibodies with different Abeta epitopes (3D6, Abeta(1-5); 266, Abeta(16-23)) and performing a 3D6 dose-response study. VAbeta and microhemorrhage were assessed using concomitant Abeta immunohistochemistry and hemosiderin detection. 3D6 prevented or cleared VAbeta in a dose-dependent manner, whereas 266 was without effect. Essentially complete absence of VAbeta was observed at the highest 3D6 dose, whereas altered morphology suggestive of ongoing clearance was seen at lower doses. The incidence of microhemorrhage was increased in the high-dose 3D6 group and limited to focal, perivascular sites. These colocalized with Abeta deposits having altered morphology and apparent clearance in the lower-dose 3D6 group. Our results suggest that passive immunization can reduce VAbeta levels, and modulating antibody dose can significantly mitigate the incidence of microhemorrhage while still preventing or reducing VAbeta. These observations raise the possibility that Abeta immunotherapy can potentially slow or halt the course of CAA development in AD that is implicated in vascular dysfunction.
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“However mAbs binding deposited Aβ are generally more effective in clearing VAβ [12].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [12]
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“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 [12]
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Self-citation
Metadata
- Authors
- Schroeter, S., Khan, K., Barbour, R., Doan, M., Chen, M., Guido, T., Gill, D., Basi, G., Schenk, D., Seubert, P., & Games, D.
- Affiliations
- Wyeth (US)
- Elan Pharmaceuticals, Inc. (Ireland) (IE)
- Corresponding author
- Games, D.
- ORCID
- Schroeter, S.
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-07-02
- Volume
- 28
- Issue
- 27
- Pages
- 6787-6793
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6670967
- OpenAlex
- W2069315029
- Cited by
- 133
- References
- 32
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 15 · 2023: 2 · 2022: 6 · 2021: 3 · 2020: 3 · 2019: 1 · 2017: 5 · 2016: 5 · 2015: 6 · 2014: 12 · 2013: 6 · 2012: 19
- FWCI
- 9.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- cerebral amyloid angiopathy, Alzheimer's disease, passive immunization, anti-amyloid beta antibodies, antibody epitope specificity, microhemorrhages, amyloid-beta clearance, PDAPP mice, hemosiderin, vascular dysfunction
- MeSH terms
- Animals, Antibodies, Epitopes, Cerebral Arteries, Cerebral Hemorrhage, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Immunization, Passive, Metabolic Clearance Rate, Mice, Transgenic, Down-Regulation, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Cerebral Amyloid Angiopathy, Treatment Outcome, Mice
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