title: Microglia activation and phagocytosis: relationship with aging and cognitive impairment in the rhesus monkey.
abstract: While cognitive decline is observed in the normal aging monkey, neurons are not lost with age. Instead, frontal white matter is lost as myelin degenerates and both correlate with age-related cognitive decline. As age-related myelin damage increases, there should be an increase in clearance of damaged myelin by microglial phagocytosis. In this study, brains of behaviorally tested rhesus monkeys were assessed using unbiased stereology to quantify the density of activated microglia (LN3 antibody positive) and phagocytic microglia (galectin-3 (Gal-3) antibody positive) in three white matter regions: the corpus callosum, cingulum bundle (CGB), and frontal white matter (FWM). LN3 cell density was significantly increased in the CGB, whereas Gal-3 cell density was significantly increased in all regions. Increases in Gal-3 cell density in the FWM were associated with cognitive impairment. In the FWM of old animals, Gal-3-positive microglia were classified by morphological subtype as ramified, hypertrophic, or amoeboid. The densities of hypertrophic and amoeboid microglia significantly correlated with cognitive impairment. Finally, microglia were double-labeled with LN3 and Gal-3 showing that 91% of Gal-3 cells were also LN3 positive, thus expressing an "activated" phenotype. Furthermore, 15% of all double-labeled cells formed phagocytic cups. Overall, these results suggest that microglia become activated in white matter with age where the majority express a phagocytic phenotype. We hypothesize that age-related phagocytic activation of microglia is a response to accumulating myelin pathology. The association of Gal-3 in the FWM with cognitive impairment may reflect regional differences in damage or dysfunction of normal clearance mechanisms.
authors.affiliation: Department of Anatomy and Neurobiology, Boston University, Boston, MA, 02118, USA. eshobin@bu.edu.|Graduate Program for Neuroscience, Boston University, Boston, MA, 02118, USA. eshobin@bu.edu.
authors.forename: Eli
authors.identifier: 0000-0001-7172-1065
authors.initials: E
authors.lastname: Shobin
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston, MA, 02144, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Bowley
authors.affiliation: Department of Anatomy and Neurobiology, Boston University, Boston, MA, 02118, USA.|Department of Pharmacology and Experimental Therapeutics, Boston University, Boston, MA, 02118, USA.
authors.forename: Larissa I
authors.initials: LI
authors.lastname: Estrada
authors.affiliation: Department of Anatomy and Neurobiology, Boston University, Boston, MA, 02118, USA.
authors.forename: Nadine C
authors.initials: NC
authors.lastname: Heyworth
authors.affiliation: Department of Anatomy and Neurobiology, Boston University, Boston, MA, 02118, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Orczykowski
authors.affiliation: Department of Anatomy and Neurobiology, Boston University, Boston, MA, 02118, USA.|Biology Department, University of Massachusetts Dartmouth, Dartmouth, MA, 02747, USA.
authors.forename: Sherri A
authors.initials: SA
authors.lastname: Eldridge
authors.affiliation: Department of Anatomy and Neurobiology, Boston University, Boston, MA, 02118, USA.
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Calderazzo
authors.affiliation: Department of Anatomy and Neurobiology, Boston University, Boston, MA, 02118, USA.
authors.forename: Farzad
authors.initials: F
authors.lastname: Mortazavi
authors.affiliation: Department of Anatomy and Neurobiology, Boston University, Boston, MA, 02118, USA.|Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, USA.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Moore
authors.affiliation: Department of Anatomy and Neurobiology, Boston University, Boston, MA, 02118, USA.
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Rosene
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D060825:Cognitive Dysfunction / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D037502:Galectin 3 / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D017628:Microglia / Q000502:physiology*; D010587:Phagocytosis / Q000502:physiology*
chemical_list: D037502:Galectin 3
keywords: Aging; Galectin-3; Inflammation; Mac-2; Macrophages; Myelin damage