Ineffective phagocytosis of amyloid-β by macrophages of Alzheimer's disease patients

Article type: Research Article

Authors: Fiala, Milan^{a; *} | Lin, Justin^a | Ringman, John^b | Kermani-Arab, Vali^c | Tsao, George^a | Patel, Amish^a | Lossinsky, Albert S.^d | Graves, Michael C.^b | Gustavson, Andrew^b | Sayre, James^e | Sofroni, Emanuela^a | Suarez, Tatiana^a | Chiappelli, Francesco^f | Bernard, George^f

Affiliations: [a] Department of Medicine, Greater LA VA Medical Center and UCLA School of Medicine, Los Angeles, CA 90095, USA | [b] Department of Neurology, UCLA School of Medicine, Los Angeles, CA 90095, USA | [c] Immuno-Biogenetic Institute, Inc, West Hills, CA 91307, USA | [d] Neural Engineering Program, Huntington Medical Research Institutes, 743 Fairmount Avenue, Pasadena, CA 91105, USA | [e] Department of Biostatistics, UCLA School of Public Health, Los Angeles, CA 90095, USA | [f] Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, CA 90095, USA

Correspondence: [*] Corresponding author: Milan Fiala, M.D., Oral Biology and Medicine, UCLA 63-090, Los Angeles, CA 90095-1668, USA. Tel.: +1 310 206 6392; Fax: +1 310 825 2042; E-mail: [email protected].

Abstract: The defective clearance of amyloid-β (Aβ) 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 Aβ but only inefficient clearance of Aβ deposits. Neurons and neuronal nuclei, respectively, express interleukin-1β and the chemokine RANTES, which could induce the inflammatory cell infiltration. To clarify the pathophysiology of Aβ clearance, we examined Aβ 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 Aβ followed by Aβ degradation or export. AD monocytes show poor differentiation and only surface uptake of Aβ 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 Aβ 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.

Keywords: macrophage/monocyte, amyloid-beta phagocytosis, macrophage apoptosis, innate immunity, inflammation and Alzheimer's disease

DOI: 10.3233/JAD-2005-7304

Journal: Journal of Alzheimer's Disease, vol. 7, no. 3, pp. 221-232, 2005