CCL2 accelerates microglia-mediated Aβ oligomer formation and progression of neurocognitive dysfunction

Tomomi Kiyota, Masaru Yamamoto, Huangui Xiong, Mary P. Lambert, William L. Klein, Howard Eliot Gendelman, Richard M. Ransohoff, Tsuneya Ikezu

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Background: The linkages between neuroinflammation and Alzheimer's disease (AD) pathogenesis are well established. What is not, however, is how specific immune pathways and proteins affect the disease. To this end, we previously demonstrated that transgenic over-expression of CCL2 enhanced microgliosis and induced diffuse amyloid plaque deposition in Tg2576 mice. This rodent model of AD expresses a Swedish b-amyloid (Ab) precursor protein mutant. Methodology/Principal Findings: We now report that CCL2 transgene expression accelerates deficits in spatial and working memory and hippocampal synaptic transmission in β-amyloid precursor protein (APP) mice as early as 2-3 months of age. This is followed by increased numbers of microglia that are seen surrounding Aβ oligomers. CCL2 does not suppress Aβ degradation. Rather, CCL2 and tumor necrosis factor-α directly facilitated Aβ uptake, intracellular Aβ oligomerization, and protein secretion. Conclusions/Significance: We posit that CCL2 facilitates Aβ oligomer formation in microglia and propose that such events accelerate memory dysfunction by affecting Aβ seeding in the brain.

Original languageEnglish (US)
Article numbere6197
JournalPloS one
Volume4
Issue number7
DOIs
StatePublished - Jul 10 2009

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Amyloid beta-Protein Precursor
neuroglia
Microglia
amyloid
Oligomers
Alzheimer Disease
Alzheimer disease
Amyloid
Amyloid Plaques
Transgenes
Short-Term Memory
Synaptic Transmission
Data storage equipment
Rodentia
Oligomerization
synaptic transmission
Proteins
protein secretion
Protein Precursors
proteins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

CCL2 accelerates microglia-mediated Aβ oligomer formation and progression of neurocognitive dysfunction. / Kiyota, Tomomi; Yamamoto, Masaru; Xiong, Huangui; Lambert, Mary P.; Klein, William L.; Gendelman, Howard Eliot; Ransohoff, Richard M.; Ikezu, Tsuneya.

In: PloS one, Vol. 4, No. 7, e6197, 10.07.2009.

Research output: Contribution to journalArticle

Kiyota, Tomomi ; Yamamoto, Masaru ; Xiong, Huangui ; Lambert, Mary P. ; Klein, William L. ; Gendelman, Howard Eliot ; Ransohoff, Richard M. ; Ikezu, Tsuneya. / CCL2 accelerates microglia-mediated Aβ oligomer formation and progression of neurocognitive dysfunction. In: PloS one. 2009 ; Vol. 4, No. 7.
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AU - Klein, William L.

AU - Gendelman, Howard Eliot

AU - Ransohoff, Richard M.

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