ArticleJournal of neuroinflammation2011
Microglial MAC1 receptor and PI3K are essential in mediating β-amyloid peptide-induced microglial activation and subsequent neurotoxicity.
Article in Journal of neuroinflammation, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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56 citing papers in PubMed, 86 citations in OpenAlex.
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- Exploration of the shared gene signatures and molecular mechanisms between Alzheimer's disease and intracranial aneurysm.Scientific reports · 2024Article
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- An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer's brains.Immunity · 2024Article
- Role of Oxidative Stress, Methionine Oxidation and Methionine Sulfoxide Reductases (MSR) in Alzheimer's Disease.Antioxidants (Basel, Switzerland) · 2023Review
- Complement C3 Enhances LPS-Elicited Neuroinflammation and Neurodegeneration Via the Mac1/NOX2 Pathway.Molecular neurobiology · 2023Article
- Reduced binding of apoE4 to complement factor H promotes amyloid-β oligomerization and neuroinflammation.EMBO reports · 2023Article
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- PI3K/AKT/mTOR signaling pathway activity in IDH-mutant diffuse glioma and clinical implications.Neuro-oncology · 2022Article
- Using Molecular Targets to Predict and Treat Aortic Aneurysms.Reviews in cardiovascular medicine · 2022Review
- Activation of the MAC1-ERK1/2-NOX2 Pathway Is Required for LPS-Induced Sustaining Reactive Microgliosis, Chronic Neuroinflammation and Neurodegeneration.Antioxidants (Basel, Switzerland) · 2022Article
- Microglial autophagy in Alzheimer's disease and Parkinson's disease.Frontiers in aging neuroscience · 2022Review
- Microglia in Alzheimer's Disease: A Favorable Cellular Target to Ameliorate Alzheimer's Pathogenesis.Mediators of inflammation · 2022Review
- A Neuron, Microglia, and Astrocyte Triple Co-culture Model to Study Alzheimer's Disease.Frontiers in aging neuroscience · 2022Article
- Microglia and Astrocytes in Alzheimer's Disease in the Context of the Aberrant Copper Homeostasis Hypothesis.Biomolecules · 2021Review
- Neuromechanobiology: An Expanding Field Driven by the Force of Greater Focus.Advanced healthcare materials · 2021Review
- Preclinical Marmoset Model for Targeting Chronic Inflammation as a Strategy to Prevent Alzheimer's Disease.Vaccines · 2021Review
- The AGE-RAGE Axis and RAGE Genetics in Chronic Obstructive Pulmonary Disease.Clinical reviews in allergy & immunology · 2021Review
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Authors and funding
8 authors at 2 institutions in 3 countries.
Funding
Abstract
backgroundβ-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.
methodsFor 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.
resultsWe 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.
conclusionsTaken 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.
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