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A Novel In Vitro Live-imaging Assay of Astrocyte-mediated Phagocytosis Using pH Indicator-conjugated Synaptosomes
Published on: February 5, 2018
Cortical reactive microglia activate astrocytes, increasing neurodegeneration in human alcohol use disorder
Fulton T Crews1, Liya Qin2, Leon Coleman3
1Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Pharmacology School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
Abstract:
Reactive microglia are associated with multiple brain diseases that may have specific disease-related phenotypes. Studies of human cortical microglia in alcohol use disorder (AUD) have characterized reactive microglial subtypes by transcriptome or histology. Preclinical studies have found proinflammatory signaling and microglia contribute to increases in alcohol drinking and preference, behaviors unique to AUD. This study of post-mortem human AUD combines microglial immunoreactivity (+IR) protein and changes in microglial gene expression (mRNA) in human orbital frontal cortex (OFC) in an effort to better characterize the reactive microglia associated with AUD. Since reactive microglia are linked to increased glial fibrillary acid protein (GFAP + IR) in reactive astrocytes, oxidative DNA damage (8-hydroxy-2'-deoxyguanosine (8-OHdG + IR), and neuron loss, these were determined as well. AUD reactive microglia were identified by increases in expression of multiple markers in the OFC compared to control moderate drinkers. Tmem119 + IR was decreased in AUD brain. Several of these microglial genes had parallel changes in + IR protein and mRNA. However, several microglial markers commonly used to identify reactive microglia did not show changes in mRNA, including Iba1, CD68, P2RY12, and CSF1R. Overall, AUD microglia show increases in monocyte phagocytic markers, but not TREM2, DAP, or complement genes. Reactive microglial markers were highly correlated with reactive astrocyte GFAP + IR, oxidative stress 8-OHdG + IR, as well as loss of neurons assessed using (Neuronal Nucleu [NeuN] and microtubule-associated protein 2 [MAP2] + IR). Mediation analysis indicated reactive microglia contribute to both reactive astrocytes and oxidative stress, but only reactive astrocytes were found to significantly contribute to loss of neurons (NeuN + IR). These findings are supported by mouse studies finding chronic ethanol exposure increases reactive astrocytes and oxidative stress that is inhibited by DREADD blockade of microglial activation. Our findings support a distinct AUD reactive microglial phenotype that activates astrocytes, contributing to AUD neurodegeneration and possibly heavy drinking.
Insights
Reactive microglia in alcohol use disorder (AUD) brains show distinct changes, activating astrocytes and contributing to neurodegeneration. These findings highlight a specific microglial phenotype in AUD.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Reactive microglia are implicated in various brain diseases, exhibiting specific phenotypes.
- Alcohol use disorder (AUD) is associated with neuroinflammation, where microglia play a key role.
- Previous studies suggest microglial involvement in AUD-related behaviors and neurobiological changes.
Purpose of the Study:
- To characterize the reactive microglia phenotype in the human orbital frontal cortex (OFC) of individuals with AUD.
- To investigate the relationship between microglial changes, reactive astrocytes, oxidative stress, and neuronal loss in AUD.
- To explore the potential role of specific microglial markers in AUD neuropathology.
Main Methods:
- Analysis of post-mortem human brain tissue from AUD and control groups.
- Assessment of microglial immunoreactivity (protein) and gene expression (mRNA) for various markers.
- Quantification of reactive astrocyte marker (GFAP), oxidative DNA damage (8-OHdG), and neuronal markers (NeuN, MAP2).
Main Results:
- AUD microglia exhibited increased expression of certain markers, with decreased Tmem119 immunoreactivity.
- Reactive microglial markers correlated with reactive astrocytes, oxidative stress, and neuronal loss.
- Mediation analysis suggested reactive microglia contribute to reactive astrocytes and oxidative stress, which in turn contribute to neuronal loss.
Conclusions:
- A distinct reactive microglia phenotype is identified in AUD brains.
- Reactive microglia in AUD activate astrocytes, contributing to neurodegeneration.
- These findings provide insights into the neurobiological mechanisms underlying AUD and its associated brain damage.
