C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation.

Autor:	Lall D; Center for Neural Science and Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA., Lorenzini I; Department of Neurobiology, Barrow Neurological Institute, 350 W. Thomas Road, Phoenix, AZ 85013, USA., Mota TA; Center for Neural Science and Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA., Bell S; Center for Neural Science and Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA., Mahan TE; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, USA., Ulrich JD; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, USA., Davtyan H; Institute for Memory Impairments and Neurological Disorders, Sue & Bill Gross Stem Cell Research Center, 3200 Gross Hall, 845 Health Sciences Road, University of California, Irvine, Irvine, CA 92697, USA., Rexach JE; Program in Neurogenetics, Department of Neurology, Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Muhammad AKMG; Center for Neural Science and Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA., Shelest O; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA., Landeros J; Center for Neural Science and Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA., Vazquez M; Center for Neural Science and Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA., Kim J; Department of Neurobiology, Barrow Neurological Institute, 350 W. Thomas Road, Phoenix, AZ 85013, USA., Ghaffari L; Department of Neurobiology, Barrow Neurological Institute, 350 W. Thomas Road, Phoenix, AZ 85013, USA., O'Rourke JG; Center for Neural Science and Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA., Geschwind DH; Program in Neurogenetics, Department of Neurology, Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Blurton-Jones M; Institute for Memory Impairments and Neurological Disorders, Sue & Bill Gross Stem Cell Research Center, 3200 Gross Hall, 845 Health Sciences Road, University of California, Irvine, Irvine, CA 92697, USA., Holtzman DM; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, USA., Sattler R; Department of Neurobiology, Barrow Neurological Institute, 350 W. Thomas Road, Phoenix, AZ 85013, USA. Electronic address: rita.sattler@barrowneuro.org., Baloh RH; Center for Neural Science and Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; Department of Neurology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA. Electronic address: robert.baloh@csmc.edu.
Jazyk:	angličtina
Zdroj:	Neuron [Neuron] 2021 Jul 21; Vol. 109 (14), pp. 2275-2291.e8. Date of Electronic Publication: 2021 Jun 15.
DOI:	10.1016/j.neuron.2021.05.020
Abstrakt:	C9orf72 repeat expansions cause inherited amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) and result in both loss of C9orf72 protein expression and production of potentially toxic RNA and dipeptide repeat proteins. In addition to ALS/FTD, C9orf72 repeat expansions have been reported in a broad array of neurodegenerative syndromes, including Alzheimer's disease. Here we show that C9orf72 deficiency promotes a change in the homeostatic signature in microglia and a transition to an inflammatory state characterized by an enhanced type I IFN signature. Furthermore, C9orf72-depleted microglia trigger age-dependent neuronal defects, in particular enhanced cortical synaptic pruning, leading to altered learning and memory behaviors in mice. Interestingly, C9orf72-deficient microglia promote enhanced synapse loss and neuronal deficits in a mouse model of amyloid accumulation while paradoxically improving plaque clearance. These findings suggest that altered microglial function due to decreased C9orf72 expression directly contributes to neurodegeneration in repeat expansion carriers independent of gain-of-function toxicities. Competing Interests: Declaration of interests R.H.B. is employed by Roche Pharmaceuticals. D.M.H. is listed as an inventor on a patent licensed by Washington University to C2N Diagnostics on the therapeutic use of anti-tau antibodies. D.M.H. co-founded and is on the scientific advisory board of C2N Diagnostics, LLC. C2N Diagnostics, LLC, has licensed certain anti-tau antibodies to AbbVie for therapeutic development. D.M.H. is on the scientific advisory board of Denali and consults for Genentech, Merck, and Cajal Neurosciences. D.M.H. and J.D.U. are listed as inventors on a provisional patent from Washington University on TREM2 antibodies. R.S. is on the scientific advisory board of Spinogenix Inc. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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