Distinct modulation of microglial amyloid β phagocytosis and migration by neuropeptidesi

Abstract

Microglial activation plays an integral role in the development and course of neurodegeneration. Although neuropeptides such as bradykinin (BK), somatostatin (SST), and endothelin (ET) are known to be important mediators of inflammation in the periphery, evidence of a similar function in brain is scarce. Using immunocytochemistry, we demonstrate the expression of receptors for BK (B1, B2 subtypes), ET (ETA, ETB subtypes) and SST (SST 2, 3, 4 subtypes) in primary microglia and microglial cell lines. Exposure of BV2 and N9, as well as primary microglial cells to BK or SST increased Aβ uptake in a concentration-dependent manner, whereas endothelin decreased Aβ uptake. This was caused by increased phagocytosis of Aβ since the rate of intracellular Aβ degradation remained unaffected. All neuropeptides increased chemotactic activity of microglia. In addition, BK reduced Aβ-induced expression of proinflammatory genes including iNOS and COX-2. ET decreased the Aβ-induced expression of monocyte chemoattractant protein 1 and interleukin-6. These results suggest that neuropeptides play an important role in chemotaxis and Aβ clearance and modulate the brain's response to neuroinflammatory processes.

Kinin B2 receptor can play a neuroprotective role in Alzheimer's disease

“…Another interesting finding of the present study was the increased Aβ deposition in KOB2Aβ mice, suggesting that B2R activation may play an important role in Aβ degradation in vivo. Supporting our data, it was shown that the concentration-dependent stimulation of BV2 and N9 cell lines or primary microglial cells by BK or endothelin increased the phagocytosis of Aβ by these cells (Fleisher-Berkovich et al, 2010).…”

Quantitative proteomics reveals that PEA15 regulates astroglial Aβ phagocytosis in an Alzheimer's disease mouse model

“…In all groups of cells, the levels of intracellular Aβ peaked at 3 h (Fig. 3B), consistent with previous results obtained using microglia [71,72]. By comparison, at 6 h, the intracellular Aβ levels were substantially lower, indicating that the rate of protein degradation far exceeded the rate of A) The gene expression levels of 6 proteins were analyzed by real-time PCR test.…”

Neuropeptides and Microglial Activation in Inflammation, Pain, and Neurodegenerative Diseases

“…Another study showed that SST dose-dependently induces A β 1–42 phagocytosis in BV-2, N9, and rat primary microglial cells, supporting a protective role for SST in the development of AD by modulating microglial function [63]. However, this study showed no effect of SST either alone or in combination with A β on IDE or on neprilysin (another enzyme involved in A β degradation) expression in BV-2 and N9 cells [63]. The discrepancies may be due to the use in the second study of a much lower concentration of SST (100 nM) versus the 0.5–10  μ M concentrations used in the first study or also to differences in incubation times before protein assessment.…”

“…The receptors were functionally active, since SST-14 affected microglial protein phosphorylation and inhibited microglial proliferation induced by granulocyte macrophage colony-stimulating factor (GM-CSF) and IL-3 [62]. Immunoreactivity for sst2, sst3, and sst4 was later detected in BV-2, N9, and mouse primary microglial cells, and SST induced migration in BV-2 and N9 cells [63]. Activation of sst2, sst3, and sst4 in neonatal rat microglia inhibited LPS-induced PGE 2 production [150], suggesting an anti-inflammatory role for SST in microglial cells.…”