| First Author | Yamamoto M | Year | 2005 |
| Journal | Am J Pathol | Volume | 166 |
| Issue | 5 | Pages | 1475-85 |
| PubMed ID | 15855647 | Mgi Jnum | J:98450 |
| Mgi Id | MGI:3578488 | Doi | 10.1016/s0002-9440(10)62364-4 |
| Citation | Yamamoto M, et al. (2005) Overexpression of Monocyte Chemotactic Protein-1/CCL2 in {beta}-Amyloid Precursor Protein Transgenic Mice Show Accelerated Diffuse {beta}-Amyloid Deposition. Am J Pathol 166(5):1475-85 |
| abstractText | 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. |
