α-1-Antichymotrypsin Promotes β-Sheet Amyloid Plaque Deposition in a Transgenic Mouse Model of Alzheimer's Disease
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Alpha(1)-antichymotrypsin (ACT), an acute-phase inflammatory protein, is an integral component of the amyloid deposits in Alzheimer's disease (AD) and has been shown to catalyze amyloid beta-peptide polymerization in vitro. We have investigated the impact of ACT on amyloid deposition in vivo by generating transgenic GFAP-ACT-expressing mice and crossing them with the PDGF-hAPP/V717F mice, which deposit amyloid in an age-dependent manner. The number of amyloid deposits measured by Congo Red birefringence was increased in the double ACT/amyloid precursor protein (APP) transgenic mice compared with transgenic mice that only expressed APP, particularly in the hippocampus where ACT expression was highest, and the increase was preceded by elevated total amyloid beta-peptide levels at an early age. Our data demonstrate that ACT promotes amyloid deposition and provide a specific mechanism by which inflammation and the subsequent upregulation of astrocytic ACT expression in AD brain contributes to AD pathogenesis.
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Inflammatory proteins such as interleukin-1β, tumor necrosis factor-α, and interferon-γ can alter APP expression, APP processing, or Aβ transport.
“Because inflammatory proteins (e.g., interleukin-1β, tumor necrosis factor–α, and interferon-γ) can alter APP expression, APP processing, or Aβ transport (47–50), the inflammatory changes caused by the deletion of Abi3 locus may have contributed to the increase in APP protein level and subsequently Aβ accumulation.”
From Deletion of <i>Abi3</i> gene locus exacerbates neuropathological features of Alzheimer’s disease in a mouse model of Aβ amyloidosis (2021) · cites this paper as [48]
The Discussion (page not provided) says IL-1 induces APP-mRNA translation and suggests that the inflammatory protein ACT may affect APP processing or, more likely, Aβ clearance. It does not specify IL-1β or establish the claimed effects for tumor necrosis factor-α or interferon-γ. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe findings extend earlier work in mouse Aβ aggregation models that pointed to a pathogenic role for C4b and Serpina3n, and genetic evidence connecting human SERPINA3 with AD risk.
“Together these data expand previous studies in mouse models of Aβ aggregation suggesting a pathogenic role for C4b and Serpina3n23,24,44,45, as well as genetic studies linking the human homologue SERPINA3 to AD risk46”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [24]
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References 53 · Cited by 137
- Authors
- Nilsson, L. N. G., Bales, K. R., DiCarlo, G., Gordon, M. N., Morgan, D., Paul, S. M., & Potter, H.
- Affiliations
- Moffitt Cancer Center (US)
- Eli Lilly (United States) (US)
- University of South Florida (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2001-03-01
- Volume
- 21
- Issue
- 5
- Pages
- 1444-1451
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6762932
- OpenAlex
- W2167754585
- Cited by
- 137
- References
- 53
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 5 · 2022: 4 · 2021: 9 · 2020: 4 · 2019: 2 · 2017: 6 · 2015: 4 · 2014: 2 · 2013: 1 · 2012: 7
- FWCI
- 7.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of South Florida
- John Douglas French Alzheimer's Foundation
- Riksbankens Jubileumsfond
- National Institutes of Health
- National Institute on Aging (R01AG009665, AG09665)
- 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
- alpha-1-antichymotrypsin, Alzheimer's disease, amyloid-beta, amyloid precursor protein, hippocampus, astrocytes, inflammation, Congo red birefringence
- MeSH terms
- alpha 1-Antichymotrypsin, Alzheimer Disease, Animals, Astrocytes, Congo Red, Crosses, Genetic, Disease Models, Animal, Glial Fibrillary Acidic Protein, Hippocampus, Humans, Mice, Transgenic, Organ Specificity, Platelet-Derived Growth Factor, Promoter Regions, Genetic, Amyloid beta-Protein Precursor, Protein Structure, Secondary, Head Injuries, Penetrating, Mice, Plaque, Amyloid
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