Alzheimer's β‐Amyloid Peptide 1–42 Induces a Phagocytic Response in Murine Microglia

Abstract

β‐Amyloid (Aβ) peptides are a key component of the senile plaques that characterize Alzheimer's disease. Cytokine‐producing microglia have been shown to be intimately associated with amyloid deposits and have also been implicated as scavengers responsible for clearing Aβ deposits. However, little is known about the initial activation of these microglia or the effect of Aβ on phagocytosis. Murine BV‐2 microglia were used to assess the effect of synthetic Aβ 1–42 on phagocytosis by quantifying uptake of fluorescent microspheres, acetylated low‐density lipoproteins, and zymosan particles by flow cytometry. Aβ 1–42 stimulated microglial phagocytosis in a time‐ and dose‐dependent manner. Aβ fibrils produced the greatest potentiation, and once activated, phagocytosis remained elevated after removal of Aβ from the cultures. Aβ‐stimulated phagocytosis could be blocked if proteoglycans were first complexed to Aβ fibrils. These data suggest that Aβ fibrils act as an immune signal to stimulate microglial phagocytosis and that extracellular matrix molecules may modify Aβ function.

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

“…Although published studies have provided evidence of fA␤ stimulation of microglial phagocytosis of microspheres and fA␤ itself in vitro (Ard et al, 1996;Kopec and Carroll, 1998;Kitamura et al, 2003), how this response was stimulated and linked to the phagocytic machinery was unexplored. We have demonstrated that fA␤ must engage each element of the multicomponent receptor complex to stimulate the phagocytic response.…”

“…The medium was changed to serum-free DMEM, and, after 3 hr, the cells were treated with 60 M (63.6 g/ml) fA␤25-35 peptide, 1 mg/ml immune IgG, or 1 mg/ml opsonized zymosan, and fluorescent microspheres coated in PBS containing 1 mg/ml BSA were then added to the wells stimulated with free ligands. The immobilized samples comprised microspheres, which were coated with the respective stimulating ligand (Kopec and Carroll, 1998). To coat the microspheres, the same concentration of stimulating ligand was added to the microspheres and placed in a 37°C incubator for 30 min.…”

“…BV-2 cells were used because they have been proven to mimic behaviors of primary microglia (Bocchini et al, 1992;Laurenzi et al, 2001) and exhibit a robust phagocytic response (Kopec and Carroll, 1998). We initially demonstrated that these cells could be stimulated to phagocytose during activation of the classical phagocytic receptors, FcR or CR3, after incubation with immune IgG or opsonized zymosan, respectively (Fig.…”

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…The observation that activated microglia are present at amyloid deposits in human AD and in animal models of this disease suggested that it might play a pathogenic role as a result of their chronic activation, although the presence of cytoplasmic Ab granules in plaque-associated glia and microglia suggest that these cells participate in the clearance of Ab ( [7,42,65,73,125,144,155,180,215,248,254,257,259]). However, this hypothesis is hard to prove using experimental models of this disease in which many pathological features occur, namely amyloid deposition, neurofibrillary tangle formation, inflammation, neuritic and neuronal loss, synaptic and neuronal dysfunction, vascular alterations [197].…”

Juzen-taiho-to, an Herbal Medicine, Activates and Enhances Phagocytosis in Microglia/Macrophages

“…They are regarded as CNS macrophages, and many studies gave evidence that immune reaction and inflammation related with microglia play essential roles in the pathological mechanism of some neurodegenerative diseases such as Alzheimer's disease (AD), multiple sclerosis, and so on (Rogers et al 1988;Raine 1994). Activated microglia have been demonstrated to play the phagocytic role with extracellular β -amyloid deposits in AD (Kopec and Carroll 1998;Weldon et al 1998). Therefore, microglia might be a therapeutic target for AD.…”