[en] Alzheimer's disease is the most prevalent type of dementia and is caused by the deposition of extracellular amyloid-beta and abnormal tau phosphorylation. Neuroinflammation has emerged as an additional pathological component. Microglia, representing the brain's major innate immune cells, play an important role during Alzheimer's. Once activated, microglia show changes in their morphology, characterized by a retraction of cell processes. Systemic inflammation is known to increase the risk for cognitive decline in human neurogenerative diseases including Alzheimer's. Here, we assess for the first time microglial changes upon a peripheral immune challenge in the context of aging and Alzheimer's in vivo, using 2-photon laser scanning microscopy. Microglia were monitored at 2 and 10 days post-challenge by lipopolysaccharide. Microglia exhibited a reduction in the number of branches and the area covered at 2 days, a phenomenon that resolved at 10 days. Systemic inflammation reduced microglial clearance of amyloid-beta in APP/PS1 mice. NLRP3 inflammasome knockout blocked many of the observed microglial changes upon lipopolysaccharide, including alterations in microglial morphology and amyloid pathology. NLRP3 inhibition may thus represent a novel therapeutic target that may protect the brain from toxic peripheral inflammation during systemic infection.
Disciplines :
Neurology
Author, co-author :
Tejera, Dario; Department of Neurodegenerative Disease and Geriatric Psychiatry, University Hospitals Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Mercan, Dilek; Department of Neurodegenerative Disease and Geriatric Psychiatry, University Hospitals Bonn, Bonn, Germany
Sanchez-Caro, Juan M; Department of Neurodegenerative Disease and Geriatric Psychiatry, University Hospitals Bonn, Bonn, Germany
Hanan, Mor; Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
Greenberg, David; Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
Soreq, Hermona ; Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
Latz, Eicke; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA ; Institute of Innate Immunity, University Hospitals Bonn, Bonn, Germany
Golenbock, Douglas; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA
HENEKA, Michael ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University Hospitals Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA
External co-authors :
yes
Language :
English
Title :
Systemic inflammation impairs microglial Aβ clearance through NLRP3 inflammasome.
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