Characterizing the Appearance and Growth of Amyloid Plaques in APP/PS1 Mice
Open accessAbstract
Amyloid plaques are primarily composed of extracellular aggregates of amyloid-β (Aβ) peptide and are a pathological signature of Alzheimer's disease. However, the factors that influence the dynamics of amyloid plaque formation and growth in vivo are largely unknown. Using serial intravital multiphoton microscopy through a thinned-skull cranial window in APP/PS1 transgenic mice, we found that amyloid plaques appear and grow over a period of weeks before reaching a mature size. Growth was more prominent early after initial plaque formation: plaques grew faster in 6-month-old compared with 10-month-old mice. Plaque growth rate was also size-related, as smaller plaques exhibited more rapid growth relative to larger plaques. Alterations in interstitial Aβ concentrations were associated with changes in plaque growth. Parallel studies using multiphoton microscopy and in vivo microdialysis revealed that pharmacological reduction of soluble extracellular Aβ by as little as 20–25% was associated with a dramatic decrease in plaque formation and growth. Furthermore, this small reduction in Aβ synthesis was sufficient to reduce amyloid plaque load in 6-month-old but not 10-month-old mice, suggesting that treatment early in disease pathogenesis may be more effective than later treatment. In contrast to thinned-skull windows, no significant plaque growth was observed under open-skull windows, which demonstrated extensive microglial and astrocytic activation. Together, these findings indicate that individual amyloid plaque growth in vivo occurs over a period of weeks and may be influenced by interstitial Aβ concentration as well as reactive gliosis.
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The concentration of soluble Aβ in the ISF throughout life is closely associated with the amount of Aβ that ultimately deposits in the extracellular space of the brain.
“The concentration of soluble Aβ in the ISF throughout life has been shown to be closely associated with the amount of Aβ that ultimately deposits in the extracellular space of the brain (29-31).”
From Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance (2011) · cites this paper as [30]
The Discussion links soluble ISF Aβ concentration to plaque growth in APP/PS1 mice and reports that brain regions with higher ISF Aβ early in life later develop plaque pathology. The Introduction says soluble Aβ is present throughout life, but the paper does not establish a close, lifelong association between its concentration and the total amount ultimately deposited. (LLM, conf=0.82)
Experimental — accuracy not yet measuredSoluble ISF Aβ closely reflects extracellular pools of Aβ.
“Because soluble ISF Aβ has been shown to closely reflect extracellular pools of Aβ (29-31)”
From Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance (2011) · cites this paper as [30]
In in vivo model systems, similar magnitudes of Aβ reductions are sufficient to prevent or halt Aβ plaque accumulation.
“In in vivo model systems, similar magnitudes of Aβ reductions are sufficient to prevent or halt Aβ plaque accumulation (53, 54).”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [54]
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- Authors
- Yan, P., Bero, A. W., Cirrito, J. R., Xiao, Q., Hu, X., Wang, Y., Gonzales, E., Holtzman, D. M., & Lee, J.-M.
- Affiliations
- Washington University in St. Louis (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-08-26
- Volume
- 29
- Issue
- 34
- Pages
- 10706-10714
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2756291
- OpenAlex
- W2151380506
- Cited by
- 264
- References
- 8
- Citations by year
- 2026: 12 · 2025: 11 · 2024: 17 · 2023: 13 · 2022: 11 · 2021: 12 · 2020: 17 · 2019: 11 · 2018: 14 · 2017: 13 · 2016: 15 · 2015: 14 · 2014: 16 · 2013: 15 · 2012: 21
- FWCI
- 15.96
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Health Assistance Foundation
- Eli Lilly and Company
- Cure Alzheimer's Fund
- Hope Center for Neurological Disorders (P30 NS057105)
- National Institutes of Health (AG13956, R37 AG13956, NS057105)
- National Institute on Aging (R37AG13956, R37AG013956)
- National Institute of Neurological Disorders and Stroke (P30NS057105, R01NS067905, R01NS048283, P01NS032636)
- 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
- amyloid plaques, amyloid-beta, Alzheimer's disease, APP/PS1 mice, plaque progression, plaque formation, early treatment, reactive gliosis, microglial activation, astrocyte activation, in vivo microdialysis, intravital multiphoton microscopy
- MeSH terms
- Age Factors, Alzheimer Disease, Analysis of Variance, Animals, Brain, Diagnostic Imaging, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Female, Gliosis, Male, Mice, Transgenic, Time Factors, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Microdialysis, Photons, Mice, Presenilin-1, Amyloid Precursor Protein Secretases, Plaque, Amyloid
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