Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine
| Autor: | Tommy Regen, Daniel Jardanhazi-Kurutz, Fabian Nadrigny, Uwe-Karsten Hanisch, Markus P. Kummer, Lucia Dumitrescu-Ozimek, Michael T. Heneka, Ana Martinez-Hernandez, Frank Kirchhoff, Jochen Walter, Dick Terwel |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Pathology
Chemokine Transcription Genetic metabolism [Recombinant Proteins] genetics [Alzheimer Disease] metabolism [Microglia] drug effects [Microglia] pathology [Alzheimer Disease] Amyloid beta-Protein Precursor Mice Norepinephrine pathology [Brain] Cell Movement metabolism [Amyloid beta-Protein Precursor] drug effects [Cell Movement] metabolism [Inflammation] Multidisciplinary Microglia pathology [Microglia] Brain Recombinant Proteins genetics [Recombinant Proteins] medicine.anatomical_structure genetics [Amyloid beta-Protein Precursor] Cytokines Female Locus Coeruleus ddc:500 physiology [Phagocytosis] medicine.symptom Chemokines physiology [Cell Movement] metabolism [Alzheimer Disease] medicine.drug medicine.medical_specialty Phagocytosis metabolism [Amyloid beta-Peptides] Inflammation Mice Transgenic deficiency [Norepinephrine] Biology drug effects [Phagocytosis] In Vitro Techniques metabolism [Locus Coeruleus] Cell Line genetics [Inflammation] Alzheimer Disease medicine Animals Humans biosynthesis [Chemokines] Neuroinflammation pathology [Inflammation] pathology [Locus Coeruleus] metabolism [Norepinephrine] Amyloid beta-Peptides Locus Ceruleus biosynthesis [Cytokines] Disease Models Animal metabolism [Brain] pharmacology [Norepinephrine] biology.protein Locus coeruleus |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America 107(13), 6058-6063 (2010). doi:10.1073/pnas.0909586107 Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 |
| DOI: | 10.1073/pnas.0909586107 |
| Popis: | Locus ceruleus (LC)-supplied norepinephrine (NE) suppresses neuroinflammation in the brain. To elucidate the effect of LC degeneration and subsequent NE deficiency on Alzheimer's disease pathology, we evaluated NE effects on microglial key functions. NE stimulation of mouse microglia suppressed Abeta-induced cytokine and chemokine production and increased microglial migration and phagocytosis of Abeta. Induced degeneration of the locus ceruleus increased expression of inflammatory mediators in APP-transgenic mice and resulted in elevated Abeta deposition. In vivo laser microscopy confirmed a reduced recruitment of microglia to Abeta plaque sites and impaired microglial Abeta phagocytosis in NE-depleted APP-transgenic mice. Supplying the mice the norepinephrine precursor L-threo-DOPS restored microglial functions in NE-depleted mice. This indicates that decrease of NE in locus ceruleus projection areas facilitates the inflammatory reaction of microglial cells in AD and impairs microglial migration and phagocytosis, thereby contributing to reduced Abeta clearance. Consequently, therapies targeting microglial phagocytosis should be tested under NE depletion. |
| Databáze: | OpenAIRE |
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