Robust amyloid clearance in a mouse model of Alzheimer’s disease provides novel insights into the mechanism of amyloid-β immunotherapy
Open accessAbstract
Many new therapeutics for Alzheimer's disease delay the accumulation of amyloid-β (Aβ) in transgenic mice, but evidence for clearance of preexisting plaques is often lacking. Here, we demonstrate that anti-Aβ immunotherapy combined with suppression of Aβ synthesis allows significant removal of antecedent deposits. We treated amyloid-bearing tet-off APP (amyloid precursor protein) mice with doxycycline to suppress transgenic Aβ production before initiating a 12 week course of passive immunization. Animals remained on doxycycline for 3 months afterward to assess whether improvements attained during combined treatment could be maintained by monotherapy. This strategy reduced amyloid load by 52% and Aβ42 content by 28% relative to pretreatment levels, with preferential clearance of small deposits and diffuse Aβ surrounding fibrillar cores. We demonstrate that peripherally administered anti-Aβ antibody crossed the blood-brain barrier, bound to plaques, and was still be found associated with a subset of amyloid deposits many months after the final injection. Antibody accessed the brain independent of plasma Aβ levels, where it enhanced microglial internalization of aggregated Aβ. Our data support a mechanism by which passive immunization acts centrally to stimulate microglial phagocytosis of aggregated Aβ, but is opposed by the continued aggregation of newly secreted Aβ. By arresting the production of Aβ, combination therapy allows microglial clearance to work from a static amyloid burden toward a significant reduction in plaque load. Our findings suggest that combining two therapeutic approaches currently in clinical trials may improve neuropathological outcome over either alone.
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Recruitment and activation of microglia around plaques and subsequent Aβ degradation/clearance have been proposed as one of the mechanisms by which Aβ immunotherapy decreases amyloid levels.
“Recruitment and activation of microglia around plaques and subsequent Aβ degradation/clearance have been proposed as one of the mechanisms by which Aβ immunotherapy decreases amyloid levels (Bard et al., 2000; Koenigsknecht-Talboo et al., 2008; Wang et al., 2011).”
From Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis (2012) · cites this paper as Wang et al., 2011
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Cites
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ResultNeuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report
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“Caution in the potential use of combination therapy Recent studies in multiple lines of APP transgenic mice have shown that repeated injections with anti-A antibodies can increase vascular amyloid and microhemorrhage (Thakker et al., 2009) (but see Schroeter et al., 2008).”
BackgroundRodent Aβ Modulates the Solubility and Distribution of Amyloid Deposits in Transgenic Mice
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“Hemi-forebrain samples were prepared for analysis of A levels by twostep sequential extraction using 2% SDS followed by 70% formic acid (FA) as previously described (Jankowsky et al., 2007).”
MethodInfluentialSelf-citationInsights into the mechanisms of action of anti‐Aβ antibodies in Alzheimer's disease mouse models
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“Immunohistochemical (IHC) stains for Iba1, CD68, and Gfap were performed at NeuroScience Associates as described previously (Wang et al., 2011), and CD68-stained sections were counterstained with Nissl (0.05% thionine/0.08 M acetate buffer, pH 4.5).”
MethodInfluentialAlzheimer’s Disease: Exploring the Landscape of Cognitive Decline
Tenchov, R., Sasso, J. M., & Zhou, Q. A. (2024) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.4c00339 · Cited by 170 · see citing works
Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis
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“Among them, recruitment and activation of microglia triggered by antibody in the brain appears to be one of main underlying mechanisms (Koenigsknecht-Talboo et al., 2008; Wang et al., 2011).”
BackgroundMicroglia-Mediated Neuroprotection, TREM2, and Alzheimer’s Disease: Evidence From Optical Imaging
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Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer’s disease–like mice
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NPT088 reduces both amyloid‐β and tau pathologies in transgenic mice
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- Authors
- Wang, A., Das, P., Switzer, R. C., Golde, T. E., & Jankowsky, J. L.
- Affiliations
- Rice University (US)
- Baylor College of Medicine (US)
- University of Florida (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-03-16
- Volume
- 31
- Issue
- 11
- Pages
- 4124-4136
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3074951
- OpenAlex
- W2009390338
- Cited by
- 118
- References
- 19
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 6 · 2023: 6 · 2022: 6 · 2021: 4 · 2020: 4 · 2019: 8 · 2018: 6 · 2017: 6 · 2016: 12 · 2015: 9 · 2014: 15 · 2013: 9 · 2012: 12
- FWCI
- 8.51
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association (NIRG 062582)
- California Institute of Technology
- National Institutes of Health (DP2OD001734)
- National Institute on Aging (K01AG026144, R01AG018454)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, amyloid-beta, passive immunotherapy, anti-amyloid antibodies, amyloid plaque clearance, microglial phagocytosis, doxycycline, amyloid-beta 42, blood-brain barrier, combination therapy, amyloid fibril formation
- MeSH terms
- Alzheimer Disease, Analysis of Variance, Animals, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Hippocampus, Immunization, Passive, Immunohistochemistry, Mice, Transgenic, Blotting, Western, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Treatment Outcome, Mice, Plaque, Amyloid
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