Xiuzhe Wang1, Mingqin Zhu1, Erik Hjorth1, Veronica Cortés-Toro1, Helga Eyjolfsdottir2, Caroline Graff2, Inger Nennesmo3, Jan Palmblad4, Maria Eriksdotter2, Kumar Sambamurti5, Jonathan M Fitzgerald6, Charles N Serhan6, Ann-Charlotte Granholm5, Marianne Schultzberg7. 1. Department of Neurobiology, Care Sciences and Society, Section of Neurodegeneration, Karolinska Institutet, Stockholm, Sweden. 2. Department of Neurobiology, Care Sciences and Society, Section of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden. 3. Department of Laboratory Medicine, Section of Pathology, Karolinska Institutet, Stockholm, Sweden. 4. Department of Medicine, Karolinska Institutet, Stockholm, Sweden. 5. Department of Neurosciences and the Center on Aging, Medical University of South Carolina, Charleston, SC, USA. 6. Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 7. Department of Neurobiology, Care Sciences and Society, Section of Neurodegeneration, Karolinska Institutet, Stockholm, Sweden. Electronic address: marianne.schultzberg@ki.se.
Abstract
BACKGROUND: Resolution is the final stage of the inflammatory response, when restoration of tissue occurs. Failure may lead to chronic inflammation, which is known as part of the pathology in the brain of individuals with Alzheimer's disease (AD). METHODS: Specialized pro-resolving mediators (SPMs), receptors, biosynthetic enzyme, and downstream effectors involved in resolution were analyzed in postmortem hippocampal tissue from AD patients and non-AD subjects. SPMs were analyzed in cerebrospinal fluid (CSF). RESULTS: SPMs and SPM receptors were detected in the human brain. Levels of the SPM lipoxin A4 (LXA4) were reduced in AD, both in the CSF and hippocampus. An enzyme involved in LXA4 synthesis and two SPM receptors were elevated in AD brains. LXA4 and RvD1 levels in CSF correlated with Mini-Mental State Examination (MMSE) scores. CONCLUSIONS: A resolution pathway exists in the brain and the alterations described herein strongly suggest a dysfunction of this pathway in AD. MMSE correlations suggest a connection with cognitive function in AD.
BACKGROUND: Resolution is the final stage of the inflammatory response, when restoration of tissue occurs. Failure may lead to chronic inflammation, which is known as part of the pathology in the brain of individuals with Alzheimer's disease (AD). METHODS: Specialized pro-resolving mediators (SPMs), receptors, biosynthetic enzyme, and downstream effectors involved in resolution were analyzed in postmortem hippocampal tissue from ADpatients and non-AD subjects. SPMs were analyzed in cerebrospinal fluid (CSF). RESULTS: SPMs and SPM receptors were detected in the human brain. Levels of the SPM lipoxin A4 (LXA4) were reduced in AD, both in the CSF and hippocampus. An enzyme involved in LXA4 synthesis and two SPM receptors were elevated in AD brains. LXA4 and RvD1 levels in CSF correlated with Mini-Mental State Examination (MMSE) scores. CONCLUSIONS: A resolution pathway exists in the brain and the alterations described herein strongly suggest a dysfunction of this pathway in AD. MMSE correlations suggest a connection with cognitive function in AD.
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