Overexpression of monocyte chemotactic protein-1/ CCL2 in β-amyloid precursor protein transgenic mice show accelerated diffuse β-amyloid deposition

Masaru Yamamoto, Masahide Horiba, James L. Buescher, Dereng Huang, Howard Eliot Gendelman, Richard M. Ransohoff, Tsuneya Ikezu

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109 Scopus citations

Abstract

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-β peptide (Aβ) 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 Aβ deposition was present despite increased MP accumulation around hippocampal and cortical amyloid plaques. Levels of full-length APP, its C-terminal fragment, and Aβ-degrading enzymes (insulin-degrading enzyme and neprilysin) in APP/CCL2 and APP mice were indistinguishable. Sodium dodecyl sulfate-insoluble Aβ (an indicator of fibrillar Aβ) was increased in APP/CCL2 mice at 5 months of age. Apolipoprotein E, which enhances Aβ 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 Aβ deposition by reducing Aβ 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.

Original languageEnglish (US)
Pages (from-to)1475-1485
Number of pages11
JournalAmerican Journal of Pathology
Volume166
Issue number5
DOIs
Publication statusPublished - May 2005

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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