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

Research output: Contribution to journalArticle

109 Citations (Scopus)

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
StatePublished - May 2005

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Amyloid beta-Protein Precursor
Chemokine CCL2
Amyloid
Transgenic Mice
Microglia
Amyloid Plaques
Apolipoproteins E
Alzheimer Disease
Insulysin
Neprilysin
Glial Fibrillary Acidic Protein
Phagocytes
Protein C
Terminology
Sodium Dodecyl Sulfate
Macrophages
Brain

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Overexpression of monocyte chemotactic protein-1/ CCL2 in β-amyloid precursor protein transgenic mice show accelerated diffuse β-amyloid deposition. / Yamamoto, Masaru; Horiba, Masahide; Buescher, James L.; Huang, Dereng; Gendelman, Howard Eliot; Ransohoff, Richard M.; Ikezu, Tsuneya.

In: American Journal of Pathology, Vol. 166, No. 5, 05.2005, p. 1475-1485.

Research output: Contribution to journalArticle

Yamamoto, Masaru ; Horiba, Masahide ; Buescher, James L. ; Huang, Dereng ; Gendelman, Howard Eliot ; Ransohoff, Richard M. ; Ikezu, Tsuneya. / Overexpression of monocyte chemotactic protein-1/ CCL2 in β-amyloid precursor protein transgenic mice show accelerated diffuse β-amyloid deposition. In: American Journal of Pathology. 2005 ; Vol. 166, No. 5. pp. 1475-1485.
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