Kinetic analysis of aggregated amyloid-β peptide clearance in adult bone-marrow-derived macrophages from APP and CCL2 transgenic mice

Masaru Yamamoto, Tomomi Kiyota, Shannon M. Walsh, Tsuneya Ikezu

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Accumulating evidence suggests that bone-marrow (BM)-derived mononuclear phagocytes have an important role in the clearance of soluble and aggregated amyloid-β peptides (Aβ) in Alzheimer's disease (AD) brains. However, the exact kinetics of Aβ clearance in mononuclear phagocytes derived from transgenic animal models of AD expressing β-amyloid precursor protein (APP) mutants have been poorly characterized. We have examined whether CCL2 and APP expression affects the clearance of Aβ in conjunction with our control, acetylated low-density lipoprotein (AcLDL), using primary cultured BM-derived macrophages derived from adult APP, CCL2, APP/CCL2, and control littermates. Pulse-chase analysis demonstrated three distinct destinations for Aβ40 and AcLDL: intracellular retention, degradation, and secretion. As predicted, 50% of Aβ remained intracellularly contained even 5 days after pulse, while 40% of degraded and 14% of nondegraded Aβ were secreted. APP/CCL2 macrophages show reduced intracellular Aβ retention, along with enhanced secretion of both degraded and nondegraded Aβ. Aβ accumulation in aggresome is also partially reduced in APP/CCL2 macrophages as compared to other APP, CCL2, or control groups, suggesting impaired sorting of aggregated Aβ in aggresomes. The degradation of intracranially injected 125I-Aβ40 aggregates was also enhanced in adult APP/CCL2 mice as compared to APP littermates in vivo. These data suggest that APP and CCL2 synergistically enhance BM-derived macrophage-mediated clearance of Aβ. In contrast, the clearance of AcLDL by BM-derived macrophages was not significantly enhanced by the presence of either APP or CCL2.

Original languageEnglish (US)
Pages (from-to)213-221
Number of pages9
JournalJournal of Neuroimmune Pharmacology
Volume2
Issue number2
DOIs
StatePublished - Jun 2007

Keywords

  • APP
  • Beta-amyloid
  • Bone marrow-macrophage
  • CCL2
  • Degradation
  • Phagocytosis

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

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