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Kinetic Analysis of Aggregated Amyloid-β Peptide Clearance in Adult Bone-marrow-derived Macrophages from APP and CCL2 Transgenic Mice

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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.

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Abbreviations

Aβ:

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

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Acknowledgements

We thank Dr. K. Ashe for providing Tg2576 mice; Dr. Richard Ransohoff for providing JE-95 mice; Dr. Y. Enose for the instruction of tissue culture; Dr. J. Kipnis for critical reading of the manuscript; and J. Buescher for editing, animal maintenance, and genotyping. This work is supported by Vada Oldfield Alzheimer Research Foundation and NIH NS043985 (TI).

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Authors and Affiliations

  1. The Center for Neurovirology and Neurodegenerative Disorders, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985880 Nebraska Medical Center, Omaha, NE, 68198-5880, USA

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

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  1. Masaru Yamamoto
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  2. Tomomi Kiyota
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  3. Shannon M. Walsh
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  4. Tsuneya Ikezu
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Correspondence to Tsuneya Ikezu.

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Yamamoto, M., Kiyota, T., Walsh, S.M. et al. Kinetic Analysis of Aggregated Amyloid-β Peptide Clearance in Adult Bone-marrow-derived Macrophages from APP and CCL2 Transgenic Mice. Jrnl Neuroimmune Pharm 2, 213–221 (2007). https://doi.org/10.1007/s11481-006-9049-8

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