Journal of Neuroimmune Pharmacology

, Volume 2, Issue 2, pp 213–221

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
Original Article

DOI: 10.1007/s11481-006-9049-8

Cite this article as:
Yamamoto, M., Kiyota, T., Walsh, S.M. et al. Jrnl Neuroimmune Pharm (2007) 2: 213. doi:10.1007/s11481-006-9049-8

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.

Keywords

APP beta-amyloid bone marrow-macrophage CCL2 degradation phagocytosis 

Abbreviations

amyloid β-peptide

AcLDL

acetylated low-density lipoprotein

AD

Alzheimer’s disease

APP

β-amyloid precursor protein

BM

bone marrow

PS

presenilin

WT

wild type

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Masaru Yamamoto
    • 1
  • Tomomi Kiyota
    • 1
  • Shannon M. Walsh
    • 1
  • Tsuneya Ikezu
    • 1
  1. 1.The Center for Neurovirology and Neurodegenerative Disorders, Department of Pharmacology and Experimental NeuroscienceUniversity of Nebraska Medical CenterOmahaUSA