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(American Journal of Pathology. 2005;166:1475-1485.)
© 2005 American Society for Investigative Pathology

Overexpression of Monocyte Chemotactic Protein-1/CCL2 in ß-Amyloid Precursor Protein Transgenic Mice Show Accelerated Diffuse ß-Amyloid Deposition

Masaru Yamamoto^*¶, Masahide Horiba^*, James L. Buescher^*¶, DeReng Huang, Howard E. Gendelman^*¶, Richard M. Ransohoff and Tsuneya Ikezu^*¶

From the Center for Neurovirology and Neurodegenerative Disorders^* and the Departments of Pharmacology,^¶ Internal Medicine, and Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska; and the Department of Neurosciences, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio

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