title: Microglia demonstrate age-dependent interaction with amyloid-β fibrils.
abstract: Alzheimer's disease (AD) is an age-associated disease characterized by increased accumulation of extracellular amyloid-β (Aβ) plaques within the brain. Histological examination has also revealed profound microglial activation in diseased brains often in association with these fibrillar peptide aggregates. The paradoxical presence of increased, reactive microglia yet accumulating extracellular debris suggests that these cells may be phagocytically compromised during disease. Prior work has demonstrated that primary microglia from adult mice are unable to phagocytose fibrillar Aβ1-42 in vitro when compared to microglia cultured from early postnatal animals. These data suggest that microglia undergo an age-associated decrease in microglial ability to interact with Aβ fibrils. In order to better define a temporal profile of microglia-Aβ interaction, acutely isolated, rather than cultured, microglia from 2 month, 6 month, and postnatal day 0 C57BL/6 mice were compared. Postnatal day 0 microglia demonstrated a CD47 dependent ability to phagocytose Aβ fibrils that was lost by 6 months. This corresponded with the ability of postnatal day 0 but not adult microglia to decrease Aβ immunoreactive plaque load from AD sections in vitro. In spite of limited Aβ uptake ability, adult microglia had functional phagocytic uptake of bacterial bioparticles and demonstrated the ability to adhere to both Aβ plaques and in vitro fibrillized Aβ. These data demonstrate a temporal profile of specifically Aβ-microglia interaction with a critical developmental period at 6 months in which cells remain able to interact with Aβ fibrils but lose their ability to phagocytose it.
authors.affiliation: Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58203-9037, USA.
authors.forename: Angela Marie
authors.initials: AM
authors.lastname: Floden
authors.forename: Colin Kelly
authors.initials: CK
authors.lastname: Combs
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000375:Aging; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000925:Anticoagulants / Q000494:pharmacology; D001921:Brain / Q000166:cytology; D018955:CD36 Antigens / Q000378:metabolism; D051928:CD47 Antigen / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology*; D011134:Polysaccharides / Q000494:pharmacology; D000067759:Receptor for Advanced Glycation End Products; D044042:Receptors, Formyl Peptide / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid; D016229:Amyloid beta-Peptides; D000925:Anticoagulants; D018955:CD36 Antigens; D051928:CD47 Antigen; D016207:Cytokines; D004791:Enzyme Inhibitors; D052118:Lysosomal-Associated Membrane Protein 1; D010446:Peptide Fragments; D011134:Polysaccharides; D000067759:Receptor for Advanced Glycation End Products; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; C075222:amyloid beta-protein (1-42); C481578:formyl peptide receptor 2, mouse; C007789:fucoidan; C115472:Cyfip1 protein, mouse