Kinetic analysis of aggregated amyloid-beta peptide clearance in adult bone-marrow-derived macrophages from APP and CCL2 transgenic mice.
Accumulating evidence suggests that bone-marrow (BM)-derived mononuclear phagocytes have an important role in the clearance of soluble and aggregated amyloid-beta peptides (Abeta) in Alzheimer's disease (AD) brains. However, the exact kinetics of Abeta clearance in mononuclear phagocytes derived from transgenic animal models of AD expressing beta-amyloid precursor protein (APP) mutants have been poorly characterized. We have examined whether CCL2 and APP expression affects the clearance of Abeta 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 Abeta40 and AcLDL: intracellular retention, degradation, and secretion. As predicted, 50% of Abeta remained intracellularly contained even 5 days after pulse, while 40% of degraded and 14% of nondegraded Abeta were secreted. APP/CCL2 macrophages show reduced intracellular Abeta retention, along with enhanced secretion of both degraded and nondegraded Abeta. Abeta 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 Abeta in aggresomes. The degradation of intracranially injected (125)I-Abeta40 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 Abeta. In contrast, the clearance of AcLDL by BM-derived macrophages was not significantly enhanced by the presence of either APP or CCL2.
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. tikezu@unmc.edu
Masaru
M
Yamamoto
Tomomi
T
Kiyota
Shannon M
SM
Walsh
Tsuneya
T
Ikezu
D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000235:genetics / Q000493:pharmacokinetics*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics* / Q000493:pharmacokinetics*; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics* / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018932:Chemokine CCL2