1. Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine
- Author
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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, and Dick Terwel
- Subjects
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 - Abstract
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.
- Published
- 2010
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