| Summary: | <p>Abstract</p> <p>Background</p> <p>β-Amyloid peptide (Aβ) is a major protein in the brain associated with Alzheimer's and Parkinson's diseases. The purpose of this study was to investigate the role of macrophage antigen-1 (MAC1) receptor, an integrin scavenger receptor in microglia, and subsequent signaling events in mediating Aβ-induced neurotoxicity. We have previously reported that NADPH oxidase (PHOX) on microglia and superoxide produced by PHOX are critical for Aβ-induced loss of dopaminergic neurons. However, the upstream signaling pathway of superoxide production remains unclear.</p> <p>Methods</p> <p>For the <it>in vitro </it>study, mesencephalic neuron-glia cultures and microglia-enriched cultures from mice deficient in the MAC1 receptor (MAC1<sup>-/-</sup>) and wild type controls were used to investigate the role of MAC1 receptor in Aβ-induced neurotoxicity and the role of phosphoinositide-3 kinase (PI3K) in the signal pathway between MAC1 receptor and PHOX. For the <it>in vivo </it>study, Aβ was injected into the substantia nigra of MAC1<sup>-/- </sup>mice and wild type mice to confirm the role of MAC1 receptor.</p> <p>Results</p> <p>We found that Aβ-induced activation of microglia, activation of PHOX, generation of superoxide and other reactive oxygen species, and loss of dopaminergic neurons were decreased in MAC1<sup>-/- </sup>cultures compared to MAC1<sup>+/+ </sup>cultures. In MAC1<sup>-/- </sup>mice, dopaminergic neuron loss in response to Aβ injection into the substantia nigra was reduced relative to MAC1<sup>+/+ </sup>mice. Thus, MAC1 receptor-mediated PHOX activation and increased superoxide production are associated with Aβ-induced neurotoxicity. PI3K activation was one downstream step in MAC1 signaling to PHOX and played an important role in Aβ-induced neurotoxicity. In microglia-enriched cultures from MAC1<sup>-/- </sup>mice, Aβ-induced activation of PI3K (phosphorylation of target proteins and PIP<sub>3 </sub>production) was reduced relative to MAC1<sup>+/+ </sup>cultures.</p> <p>Conclusions</p> <p>Taken together, our data demonstrate that Aβ activates MAC1 receptor to increase the activity of PI3K, which in turn phosphorylates p47<sup><it>phox</it></sup>, triggers the translocation of cytosolic subunits of PHOX to microglia membrane, increases PHOX activation and the subsequent production of superoxide and causes neurotoxicity.</p>
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