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

Authors

• Deepti Lall, 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.
• Ileana Lorenzini, Department of Neurobiology, Barrow Neurological Institute, 350 W. Thomas Road, Phoenix, AZ 85013, USA.
• Thomas A. Mota, 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.
• Shaughn Bell, 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.
• Thomas E. Mahan, Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, USA.
• Jason D. Ulrich, Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, USA.
• Hayk Davtyan, 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.
• Jessica E. Rexach, 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.
• A K. Muhammad, 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.
• Oksana Shelest, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
• Jesse Landeros, 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.
• Michael Vazquez, 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.
• Junwon Kim, Department of Neurobiology, Barrow Neurological Institute, 350 W. Thomas Road, Phoenix, AZ 85013, USA.
• Layla Ghaffari, Department of Neurobiology, Barrow Neurological Institute, 350 W. Thomas Road, Phoenix, AZ 85013, USA.
• Jacqueline Gire O'Rourke, 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.
• Daniel H. Geschwind, 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.
• Mathew Blurton-Jones, 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.
• David M. Holtzman, Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, USA.
• Rita Sattler, Department of Neurobiology, Barrow Neurological Institute, 350 W. Thomas Road, Phoenix, AZ 85013, USA. Electronic address: rita.sattler@barrowneuro.org.Follow
• Robert H. Baloh, 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.

Document Type

Article

Abstract

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.

Keywords

Alzheimer’s disease, C9orf72, amyotrophic lateral sclerosis, frontotemporal dementia, microglia, neurodegeneration

Medical Subject Headings

Aging (genetics, metabolism, pathology); Amyloid (genetics, metabolism); Animals; C9orf72 Protein (genetics, metabolism); DNA Repeat Expansion; Disease Models, Animal; Lysosomes (metabolism); Mice; Mice, Knockout; Microglia (metabolism); Synapses (metabolism, pathology)

Publication Date

7-21-2021

Publication Title

Neuron

E-ISSN

1097-4199

Volume

109

Issue

14

First Page

2275

Last Page

2291.e8

PubMed ID

34133945

Digital Object Identifier (DOI)

10.1016/j.neuron.2021.05.020

Recommended Citation

Lall, Deepti; Lorenzini, Ileana; Mota, Thomas A.; Bell, Shaughn; Mahan, Thomas E.; Ulrich, Jason D.; Davtyan, Hayk; Rexach, Jessica E.; Muhammad, A K.; Shelest, Oksana; Landeros, Jesse; Vazquez, Michael; Kim, Junwon; Ghaffari, Layla; O'Rourke, Jacqueline Gire; Geschwind, Daniel H.; Blurton-Jones, Mathew; Holtzman, David M.; Sattler, Rita; and Baloh, Robert H., "C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation" (2021). Translational Neuroscience. 1357.
https://scholar.barrowneuro.org/neurobiology/1357