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Published on: April 13, 2017
Microglial MAC1 receptor and PI3K are essential in mediating β-amyloid peptide-induced microglial activation and
Dan Zhang1, Xiaoming Hu, Li Qian
1Laboratory of Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. danzhang@imm.ac.cn
Background:
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.
Methods:
For the in vitro study, mesencephalic neuron-glia cultures and microglia-enriched cultures from mice deficient in the MAC1 receptor (MAC1-/-) 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 in vivo study, Aβ was injected into the substantia nigra of MAC1-/- mice and wild type mice to confirm the role of MAC1 receptor.
Results:
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-/- cultures compared to MAC1+/+ cultures. In MAC1-/- mice, dopaminergic neuron loss in response to Aβ injection into the substantia nigra was reduced relative to MAC1+/+ 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-/- mice, Aβ-induced activation of PI3K (phosphorylation of target proteins and PIP3 production) was reduced relative to MAC1+/+ cultures.
Conclusions:
Taken together, our data demonstrate that Aβ activates MAC1 receptor to increase the activity of PI3K, which in turn phosphorylates p47phox, triggers the translocation of cytosolic subunits of PHOX to microglia membrane, increases PHOX activation and the subsequent production of superoxide and causes neurotoxicity.
Insights
Beta-amyloid peptide (Aβ) triggers neurotoxicity by activating the MAC1 receptor in microglia, leading to increased superoxide production. This study clarifies the signaling pathway involving PI3K, crucial for Aβ-induced dopaminergic neuron loss.
Area of Science:
- Neuroscience
- Immunology
Background:
- Beta-amyloid peptide (Aβ) is implicated in neurodegenerative diseases like Alzheimer's and Parkinson's.
- Microglia, the brain's immune cells, play a role in Aβ-induced neurotoxicity.
- The upstream signaling pathway for NADPH oxidase (PHOX) activation by Aβ remains unclear.
Purpose of the Study:
- To investigate the role of the macrophage antigen-1 (MAC1) receptor in mediating Aβ-induced neurotoxicity.
- To elucidate the signaling pathway connecting MAC1 receptor activation to PHOX-mediated superoxide production.
Main Methods:
- In vitro studies used MAC1 receptor-deficient (MAC1-/-) and wild-type (MAC1+/+) mouse microglia cultures.
- In vivo studies involved injecting Aβ into the substantia nigra of MAC1-/- and MAC1+/+ mice.
- Phosphoinositide-3 kinase (PI3K) activation was assessed as a downstream signaling event.
Main Results:
- Aβ-induced microglia activation, PHOX activation, superoxide generation, and dopaminergic neuron loss were significantly reduced in MAC1-/- models compared to controls.
- MAC1 receptor deficiency protected against Aβ-induced dopaminergic neuron loss in vivo.
- PI3K activation was identified as a key downstream signaling step in the MAC1-PHOX pathway.
Conclusions:
- Aβ activates the MAC1 receptor on microglia, initiating a signaling cascade.
- This cascade involves PI3K activation, leading to PHOX activation and subsequent superoxide production, ultimately causing neurotoxicity.
- Targeting the MAC1-PI3K-PHOX pathway may offer therapeutic strategies for Aβ-related neurodegenerative diseases.
