Ineffective phagocytosis of amyloid-beta by macrophages of Alzheimer's disease patients.
The defective clearance of amyloid-beta (Abeta) in the brain of Alzheimer's disease (AD) patients is unexplained. The immunohistochemical studies of the frontal lobe and hippocampus show perivascular and intraplaque infiltration by blood-borne macrophages containing intracellular Abeta but only inefficient clearance of beta deposits. Neurons and neuronal nuclei, respectively, express interleukin-1beta and the chemokine RANTES, which could induce the inflammatory cell infiltration. To clarify the pathophysiology ofbeta clearance, we examined Abeta phagocytosis by monocytes and macrophages isolated from the blood of age-matched patients and controls. Control monocytes display excellent differentiation into macrophages and intracellular phagocytosis of Abeta followed by beta degradation or export. AD monocytes show poor differentiation and only surface uptake of Abeta and suffer apoptosis. HLA DR and cyclooxygenase-2 are abnormally expressed on neutrophils and monocytes of AD patients. AD patients have higher levels of intracellular cytokines compared to controls. Thus Abeta clearance is not restricted to brain microglia and involves systemic innate immune responses. In AD, however, macrophage phagocytosis is defective, which may elicit compensatory response by the adaptive immune system.
Fiala
Milan
M
Department of Medicine, Greater LA VA Medical Center and UCLA School of Medicine, Los Angeles, CA 90095, USA. fiala@ucla.edu
Lin
Justin
J
Ringman
John
J
Kermani-Arab
Vali
V
Tsao
George
G
Patel
Amish
A
Lossinsky
Albert S
AS
Graves
Michael C
MC
Gustavson
Andrew
A
Sayre
James
J
Sofroni
Emanuela
E
Suarez
Tatiana
T
Chiappelli
Francesco
F
Bernard
George
G
D000368:Aged; D000544:Alzheimer Disease / Q000276:immunology* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D017209:Apoptosis / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005625:Frontal Lobe / Q000276:immunology / Q000473:pathology; D006624:Hippocampus / Q000276:immunology / Q000473:pathology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D017628:Microglia / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D010587:Phagocytosis / Q000502:physiology*; D012016:Reference Values
D016229:Amyloid beta-Peptides; D016207:Cytokines