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Cited by 124Alzheimer's disease research and treatmentsIntracerebral and Subarachnoid Hemorrhage ResearchNeuroinflammation and Neurodegeneration Mechanisms

Intracerebroventricular amyloid-β antibodies reduce cerebral amyloid angiopathy and associated micro-hemorrhages in aged Tg2576 mice

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Thakker, Deepak R., Weatherspoon, Marcy R., Harrison, Jonathan, Keene, Thomas E., Lane, Deanna S., Kaemmerer, William F., Stewart, Gregory R., Shafer, Lisa L.·2009·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0813404106PMC PMC2647980
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Abstract

Although immunization against amyloid-beta (Abeta) holds promise as a disease-modifying therapy for Alzheimer disease (AD), it is associated with an undesirable accumulation of amyloid in the cerebrovasculature [i.e., cerebral amyloid angiopathy (CAA)] and a heightened risk of micro-hemorrhages. The central and peripheral mechanisms postulated to modulate amyloid with anti-Abeta immunotherapy remain largely elusive. Here, we compared the effects of prolonged intracerebroventricular (i.c.v.) versus systemic delivery of anti-Abeta antibodies on the behavioral and pathological changes in an aged Tg2576 mouse model of AD. Prolonged i.c.v. infusions of anti-Abeta antibodies dose-dependently reduced the parenchymal plaque burden, astrogliosis, and dystrophic neurites at doses 10- to 50-fold lower than used with systemic delivery of the same antibody. Both i.c.v. and systemic anti-Abeta antibodies reversed the behavioral impairment in contextual fear conditioning. More importantly, unlike systemically delivered anti-Abeta antibodies that aggravated vascular pathology, i.c.v.-infused antibodies globally reduced CAA and associated micro-hemorrhages. We present data suggesting that the divergent effects of i.c.v.-delivered anti-Abeta antibodies result from gradually engaging the local (i.e., central) mechanisms for amyloid clearance, distinct from the mechanisms engaged by high doses of anti-Abeta antibodies that circulate in the vasculature following systemic delivery. With robust efficacy in reversing AD-related pathology and an unexpected benefit in reducing CAA and associated micro-hemorrhages, i.c.v.-targeted passive immunotherapy offers a promising therapeutic approach for the long-term management of AD.

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  • Application of N-terminus specific mAbs, which like 10D5 bind epitopes exposed in Aβ parenchymal plaques and VAβ, but not mAbs, which like m266 bind the Aβ central domain and do not bind to deposited Aβ, effect increased hemorrhage incidence.

    “Thus, application of N-terminus specific mAbs, which like10D5 binds epitopes exposed in Aβ parenchymal plaques and VAβ, but not mAbs, which like m266 bind the Aβ central domain and do not bind to deposited Aβ effect increased hemorrhage incidence [64, 65].”

    From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [65]

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  • Exacerbation of VAβ associated microhemorrhages appears to be associated with propensity of anti-Aβ mAb to bind deposited Aβ.

    “Exacerbation of VAβ associated microhemorrhages appears to be associated with propensity of anti-Aβ mAb to bind deposited Aβ.”

    From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [65]

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Authors
Thakker, D. R., Weatherspoon, M. R., Harrison, J., Keene, T. E., Lane, D. S., Kaemmerer, W. F., Stewart, G. R., & Shafer, L. L.
Affiliations
  • Science and Technology (LT220) and Neuromodulation (
  • RC Electronics (United States) (US)
  • Medtronic (United States) (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2009-03-17
Volume
106
Issue
11
Pages
4501-4506
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0813404106
PMC
PMC2647980
OpenAlex
W2147493255
Cited by
124
References
18
Citations by year
2026: 3 · 2025: 1 · 2024: 2 · 2023: 5 · 2022: 5 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 8 · 2017: 7 · 2016: 5 · 2015: 10 · 2014: 13 · 2013: 5 · 2012: 8
FWCI
10.42
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
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
anti-amyloid beta antibodies, intracerebroventricular administration, cerebral amyloid angiopathy, Alzheimer's disease, Tg2576 mice, passive immunotherapy, amyloid-beta immunization, amyloid clearance, astrocyte activation, contextual fear conditioning, aged mice
MeSH terms
Age Factors, Alzheimer Disease, Animals, Antibodies, Behavior, Animal, Cerebral Hemorrhage, Fear, Immunization, Mice, Transgenic, Amyloid beta-Peptides, Cerebral Amyloid Angiopathy, Mice

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