Effects of Incorporation of Immunoglobulin G and Complement Component C1q on Uptake and Degradation of Alzheimer's Disease Amyloid Fibrils by Microglia

Abstract

Microglia are macrophage-like immune system cells found in the brain. They are associated with Alzheimer's Disease plaques, which contain fibrillar ␤-amyloid (fA␤) and other components such as complement proteins. We have shown previously that murine microglia bind and internalize fA␤ microaggregates via the type A scavenger receptor, but degradation of internalized fA␤ is significantly slower than normal degradation. In this study, we compared internalization by microglia of fA␤ microaggregates to that of anti-A␤-antibody-coated fA␤ (IgG-fA␤) microaggregates and found that the uptake of the latter is increased by about 1.5-fold versus unmodified fA␤. The endocytic trafficking of IgG-fA␤ is similar to that of fA␤ microaggregates, following an endosomal/ lysosomal pathway. We also compared the internalization of fA␤ microaggregates to that of complement protein, C1q-coated fA␤ microaggregates, and found that the levels of uptake are also increased by about 1.5-fold. Rates of degradation of both types of modified fA␤ microaggregates are unchanged compared with unmodified fA␤ microaggregates. We demonstrated by blocking studies that internalization of IgG-fA␤ is mediated by Fc receptors. These data suggest that, in vivo, several different microglial receptors may play a part in internalizing fA␤, but the involvement of other receptors may not increase the degradation of fA␤.

Microglial Phagocytosis of Fibrillar β-Amyloid through a β1Integrin-Dependent Mechanism

“…This conclusion was supported by ex vivo assays in which antibodies directed against A␤ prompted microglia cells to phagocytose plaques from brain sections in an FcR-dependent manner (Bard et al, 2000). The participation of FcR in A␤ phagocytosis is consistent with previous reports of enhanced phagocytosis of A␤-IgG conjugates in vitro (Paresce et al, 1996;Brazil et al, 2000). The requirement of FcR for removal of A␤ deposits in vivo has been contested (Das et al, 2003), and there is clear evidence that alternative mechanisms are capable of removing A␤ deposits (Wyss-Coray et al, 2002;Wilcock et al, 2004).…”

Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease

“…However, studies on scavenger receptor knockout mice indicate that this receptor does not initiate or mediate phagocytosis of A␤ in the brain [20]. On the other hand, in vitro studies suggest that this process may be mediated by microglial complement receptor C1q [7,46]. Numerous light and electron microscopic studies showing fibrillar A␤ internalization in phagosomes in cultured microglia are in striking contrast with all in vivo ultrastructural studies of microglia in human and tg mouse amyloid plaques carried out thus far.…”

“…We have observed bundles of fibrillar amyloid with unmodified morphology and immunoreactivity in cytoplasmic vacuoles of microglia up to the end of the culture period (19 days) [14]. In other studies a 10% reduction [7] partial degradation [8], and significant degradation [4] of the total amount of amyloid were observed in the presence of microglia in vitro. A␤ internalization by brain macrophages in vivo has been described in light microscopic studies.…”

Amyloid-β Peptide Remnants in AN-1792-Immunized Alzheimer's Disease Patients

“…Dissolution of fibrillar amyloid plaque cores by immunoglobulins or complement is followed by microglia/macrophage receptor-mediated uptake, limited degradation of A␤ and eventual discharge of soluble A␤ into the neuropil. 29,30 The A␤ HHQK domain, amino acid residues 13 to 16, is capable of unleashing neuroinflammation via activation of microglia, 31,32 and low molecular weight A␤ oligomers are recognized to kill neurons and impair cognitive function. 17,33 The oligomerization of A␤-protein begins intracellularly in cells derived from human brain, 16 and intraneuronal A␤ accumulation causes early cognitive impairment before the extracellular A␤ deposition in triple Tg mice.…”