| Research Abstract |
Microglia and astrocytes are sometimes found to contain granules immunopositive for in the brain tissues of patients with Alzheimer's disease(AD). To investigate the significance of such Aβ-containing glial cells, primary cultures of microglia and astrocytes from new borne rats were employed. Both microglia and astrocytes rapidly uptake Aβpeptides in culture medium. These cells accumulated Aβ intacellularly when they were cultured with μM to high nM Aβ1-42. Following elimination of Aβ from culture medium, Aβ granules gradually disappeared. Much higher concentration of Aβ1-40 was required for intracellular accumulation in microglia, indicating more effective clearance of Aβ1-40 than that of Aβ1-42. In mixed cultures of microglia and astrocytes, Aβ accumulated preferentially in microglia. Aβ uptake and intracellular accumulation in glial cells was also observed in in vivo experiments where Aβ was injected directly into the rat brain. In both in vitro and in vivo conditions, Aβ granules i
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n glial cells was 6E10(-)/4G8(+), indicating that processing of the amino-terminal portion of Aβoccurs similarly to human brain.
Addition of fresh rat serum or rat anti-serum to Aβ to culture medium suppressed accumulation of Aβ in microglia. Injection of Aβ into the cisterna magna of the macrophage scavenger receptor (MSR) Knock-out mice resulted in the accumulation of Aβ in meningeal macrophages. Binding of Aβ to microglial plasma membrane was reported to be mediated by the HHQK sequence of Aβ(Aβ13-16). However, excess amounts of HHQK peptide failed to block accumulation of Aβ in microglia in both in vitro and in vivo expeeriments. These results indicate that Aβ uptake by microglia takes place through multiple pathways and that opsonization-mediated phagocytosis is not the major pathway.
Aβ is produced continuously in the brain under physiological and pathological conditions. Except for rare cases of familial Alzheimer's disease (FAD), there is little evidence that prefers upregulation of Aβ production in the brain. Considering the effective uptake of Aβ by microglia, relative paucity of Aβ-containing glial cells in areas with a heavy Aβ-burden in the brain of AD should be an issue of intensive investigation. Less
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