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

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.

Elevated microsomal prostaglandin‐E synthase‐1 in Alzheimer's disease

“…This finding implies a potential role for mPGES-1 in microglial phagocytosis of Aβ plaques, a result consistent with that of a previous study [29]. In addition, our results indicate that mPGES-1 is constitutively expressed in human microglia.…”

β-Amyloid Stimulates Murine Postnatal and Adult Microglia Cultures in a Unique Manner

“…Lue et al (2001) have reported that 13-15 d in vitro cultures of microglia derived from human AD patients secrete elevated levels of IL-1␤, TNF␣, IL-6, and MCP-1 (monocyte chemoattractant protein 1) compared with control microglia. Others have demonstrated that peripheral blood-derived macrophages from AD patients have reduced capacity to phagocytose A␤ compared with cells from agematched controls (Fiala et al, 2005). Together, these data illustrate that adult AD microglia appear to respond fundamentally different to A␤ stimulation compared with control cells and complement our observations of differences between aged and .…”

Immune profiling of Alzheimer patients

“…For this reason AD has been always considered as a brain disease (Selkoe, 2001). Recently it was suggested that the inflammation induced by the accumulation of Aβ is not an only a local phenomenon but can induce systemic symptoms or be caused by systemic events (Britschgi and Wyss-Coray, 2007;Richartz-Salzburger et al, 2007;Fiala et al, 2005). Moreover, it is likely that Aβ is not only accumulated in the brains of AD patients, but is also present in the periphery and can be detected in the blood (Britschgi and Wyss-Coray, 2007;Mayeux et al, 2003;Sagare et al, 2011).…”