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Overexpression of Monocyte Chemotactic Protein-1/CCL2 in β-Amyloid Precursor Protein Transgenic Mice Show Accelerated Diffuse β-Amyloid Deposition
Open accessAbstract
Microglia accumulation at the site of amyloid plaques is a strong indication that microglia play a major role in Alzheimer's disease pathogenesis. However, how microglia affect amyloid-beta peptide (Abeta) deposition remains poorly understood. To address this question, we developed a novel bigenic mouse that overexpresses both amyloid precursor protein (APP) and monocyte chemotactic protein-1 (MCP-1; CCL2 in systematic nomenclature). CCL2 expression, driven by the glial fibrillary acidic protein promoter, induced mononuclear phagocyte (MP; monocyte-derived macrophage and microglial) accumulation in the brain. When APP/CCL2 transgenic mice were compared to APP mice, a fivefold increase in Abeta deposition was present despite increased MP accumulation around hippocampal and cortical amyloid plaques. Levels of full-length APP, its C-terminal fragment, and Abeta-degrading enzymes (insulin-degrading enzyme and neprilysin) in APP/CCL2 and APP mice were indistinguishable. Sodium dodecyl sulfate-insoluble Abeta (an indicator of fibrillar Abeta) was increased in APP/CCL2 mice at 5 months of age. Apolipoprotein E, which enhances Abeta deposition, was also increased (2.2-fold) in aged APP/CCL2 as compared to APP mice. We propose that although CCL2 stimulates MP accumulation, it increases Abeta deposition by reducing Abeta clearance through increased apolipoprotein E expression. Understanding the mechanisms underlying these events could be used to modulate microglial function in Alzheimer's disease and positively affect disease outcomes.
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“numerous other studies have suggested that altering the proliferation, 58 signaling, 8,9,11 and migration 7,59 of microglia directly impact development of A pathology.”
From CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer's Disease Mouse Models (2010) · cites this paper as [7]
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Metadata
- Authors
- Yamamoto, M., Horiba, M., Buescher, J. L., Huang, D., Gendelman, H. E., Ransohoff, R. M., & Ikezu, T.
- Affiliations
- University of Nebraska Medical Center (US)
- Cleveland Clinic (US)
- Corresponding author
- Ikezu, Tsuneya
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2005-05
- Volume
- 166
- Issue
- 5
- Pages
- 1475-1485
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1606401
- OpenAlex
- W2053953952
- Cited by
- 137
- References
- 62
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 6 · 2023: 3 · 2022: 6 · 2021: 5 · 2020: 6 · 2019: 5 · 2018: 4 · 2017: 4 · 2016: 3 · 2015: 3 · 2014: 10 · 2013: 13 · 2012: 8
- FWCI
- 5.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (RO1 NS32151, 2 R37 NS36126, P01 NS043985)
- University of Nebraska Medical Center
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
- MCP-1, amyloid precursor protein, amyloid-beta deposition, Alzheimer's disease, microglia, mononuclear phagocytes, macrophages, apolipoprotein E, amyloid plaques, fibrillar amyloid-beta, insulin-degrading enzyme, neprilysin, glial fibrillary acidic protein promoter
- MeSH terms
- Animals, Brain, Cerebral Cortex, Female, Hippocampus, Male, Mice, Transgenic, Phagocytes, Tissue Distribution, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Chemokine CCL2, Mice
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