Overexpression of Monocyte Chemotactic Protein-1/CCL2 in β-Amyloid Precursor Protein Transgenic Mice Show Accelerated Diffuse β-Amyloid Deposition
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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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Altering the proliferation, signaling, and migration of microglia directly impacts development of Aβ pathology.
“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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- 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
- 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
- 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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