کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
9943383 | 1573502 | 2005 | 11 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Overexpression of Monocyte Chemotactic Protein-1/CCL2 in β-Amyloid Precursor Protein Transgenic Mice Show Accelerated Diffuse β-Amyloid Deposition
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موضوعات مرتبط
علوم پزشکی و سلامت
پزشکی و دندانپزشکی
کاردیولوژی و پزشکی قلب و عروق
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چکیده انگلیسی
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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: The American Journal of Pathology - Volume 166, Issue 5, May 2005, Pages 1475-1485
Journal: The American Journal of Pathology - Volume 166, Issue 5, May 2005, Pages 1475-1485
نویسندگان
Masaru Yamamoto, Masahide Horiba, James L. Buescher, DeReng Huang, Howard E. Gendelman, Richard M. Ransohoff, Tsuneya Ikezu,