Artikel
Environment and autophagy influence the inflammatory response of microglia
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Veröffentlicht: | 14. September 2016 |
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Gliederung
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Introduction: Alzheimer’s disease (AD) is the most common neurodegenerative disorder, hallmarked by extracellular amyloid plaques (composed of amyloid-beta (Abeta) peptide), neurofibrillary tangles, neuroinflammation and neurodegeneration. The amyloid cascade hypothesis states that deposition of Abeta in the brain parenchyma is one of the crucial steps in the development of AD. Microglia, the resident immune cells of the central nervous system are involved in two aspects of AD: the removal respectively the failure of removal of extracellular Abeta by phagocytosis and the production and release of cytokines. Next to the well-established enhanced neuroinflammation in the late stages of AD, recent data suggests a role for inflammation in the development of AD as well. A candidate process involved in both neuroinflammation and removal of Abeta is autophagy. The efficiency of autophagy seems to decline during aging. In addition, autophagy is a regulatory mechanism for the inflammatory response in macrophages. Beclin1, a crucial protein for autophagy, was shown to be strongly reduced in microglia from AD patients [1].
Objectives: Based on these data we postulate that Beclin1 is a key molecule in microglia, influencing neuroinflammation.
Materials & Methods: Primary murine microglia were isolated from wildtype mice, Beclin1 heterozygous mice (Beclin1+/-) and APPPS1 mice, a well-established mouse model resembling aspects of AD pathology. Autophagy status and inflammation markers were analyzed by western blot, immunocytochemistry and ELISA.
Results: Microglia from Beclin1+/- and APPPS mice showed an impairment of autophagy compared to microglia from wildtype mice. Cytokine production and inflammatory markers were also altered.
Conclusion: Taken together, our data indicate that environment and autophagy status modulate microglia activation and may thus substantially impact AD pathology.
References
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- Lucin KM, O'Brien CE, Bieri G, Czirr E, Mosher KI, Abbey RJ, Mastroeni DF, Rogers J, Spencer B, Masliah E, Wyss-Coray T. Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer's disease. Neuron. 2013 Sep 4;79(5):873-86. DOI: 10.1016/j.neuron.2013.06.046