ArticleNeuron2021
C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation.
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Article in Neuron, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 101 papers.
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101citing papers in PubMed
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Who cites it
101 citing papers in PubMed, 144 citations in OpenAlex.
- Phase 2 study of palmitoylethanolamide combined with luteoline in frontotemporal dementia patients.Brain communications · 2025Trial
- Lysosomal dysfunction in neurodegenerative disease.Nature reviews. Neurology · 2026Review
- C9orf72-associated and sporadic FTD patient iPSC-microglia show differences in phagocytosis and gene expression.Stem cell reports · 2026Article
- Microglia heterogeneity in vascular dementia pathology.iScience · 2026Review
- The cGAS-STING pathway in inflammaging and neuroinflammation.Science China. Life sciences · 2026Review
- Dysfunctional Mitochondria in Microglia Drive Cognitive Aging and Neurodegeneration via cGAS-STING.Neuroscience bulletin · 2026Article
- The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair.The EMBO journal · 2026Article
- Microglial Dysfunction Induced by C9ORF72 Dipeptide Repeat Proteins: Biomarker and Therapeutic Perspectives.International journal of molecular sciences · 2026Review
- RAN translation as a dominant pathogenic axis in C9ORF72-associated ALS and FTD models.Molecular neurodegeneration · 2026Review
- Sex-dependent interferon signaling contributes to female-biased vulnerability in Alzheimer's disease.Journal of neuroinflammation · 2026Article
- Review
- Complement receptor 3 (CR3)-dependent microglial synapse elimination drives Parkinson's disease pathogenesis in systemic inflammation.Cell death & disease · 2026Article
- PU.1 restores microglial dysfunction caused by C9ORF72 repeat expansions in neural organoids.Brain : a journal of neurology · 2026Article
- Tui Na Acupressure Modulates Treg Immunosuppression via FoxP3/mTORC1 Signalling in ALS Mice.Immunology · 2026Article
- C9orf72 in myeloid cells prevents an inflammatory response to microbial glycogen.Cell reports · 2026Article
- Wild-typemedRxiv : the preprint server for health sciences · 2026Article
- Microglia-Neuron Interactions in Alzheimer's Disease.Current neuropharmacology · 2026Review
- Article
- From metabolism to neurodegeneration: how microglial functional reprogramming drives neurodegenerative diseases.Frontiers in molecular neuroscience · 2026Review
- Rod-shaped microglia interact with neuronal dendrites to attenuate cortical excitability during TDP-43-related neurodegeneration.Immunity · 2025Article
41 more citing papers are in PubMed but not listed here.
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Authors and funding
20 authors at 5 institutions in 1 country.
Deepti LallCenter 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 LorenziniDepartment of Neurobiology, Barrow Neurological Institute, 350 W. Thomas Road, Phoenix, AZ 85013, USA.
Thomas A MotaCenter 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 BellCenter 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 MahanDepartment 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 UlrichDepartment of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, USA.
Hayk DavtyanInstitute 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 RexachProgram 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 M Ghulam MuhammadCenter 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 ShelestBoard of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
Jesse LanderosCenter 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 VazquezCenter 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 KimDepartment of Neurobiology, Barrow Neurological Institute, 350 W. Thomas Road, Phoenix, AZ 85013, USA.
Layla GhaffariDepartment of Neurobiology, Barrow Neurological Institute, 350 W. Thomas Road, Phoenix, AZ 85013, USA.
Jacqueline Gire O'RourkeCenter 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 GeschwindProgram 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-JonesInstitute 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 HoltzmanDepartment of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, USA.
Rita SattlerDepartment of Neurobiology, Barrow Neurological Institute, 350 W. Thomas Road, Phoenix, AZ 85013, USA. Electronic address: rita.sattler@barrowneuro.org.
Robert H BalohCenter 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.
Cedars-Sinai Medical Center · USBarrow Neurological Institute · USWashington University in St. Louis · USUniversity of California, Irvine · USUniversity of California, Los Angeles · US
Funding
UC Irvine Alzheimer's Disease Research Center Induced Pluripotent Stem Cell CoreP50AG016573 · NIA · UNIVERSITY OF CALIFORNIA-IRVINE · PI LAFERLA, FRANK M · 2000 to 2019
$37.0MThe Alzheimer's Disease Research Center at the University of California, IrvineP30AG066519 · NIA · UNIVERSITY OF CALIFORNIA-IRVINE · PI Joshua Grill · 2020 to 2026
$27.9MEffect of APOE on CNS Neurons: Role of LRPRF1NS090934 · NINDS · WASHINGTON UNIVERSITY · PI HOLTZMAN, DAVID M. · 2020 to 2025
$6.5MNovel Strategies and Mechanisms to Target APOE and Alzheimer's DiseaseRF1AG047644 · NIA · WASHINGTON UNIVERSITY · PI HOLTZMAN, DAVID M., HYMAN, BRADLEY T. · 2019 to 2019
$3.8MEffect of APOE on CNS Neurons: Role of LRPR01NS090934 · NINDS · WASHINGTON UNIVERSITY · PI HOLTZMAN, DAVID M. · 2014 to 2018
$3.0MUsing human iPSC derived microglia and chimeric models to examine the role of PLCG2 in Alzheimers diseaseR01AG061895 · NIA · UNIVERSITY OF CALIFORNIA-IRVINE · PI DAVTYAN, HAYK · 2018 to 2022
$2.9MTranslational Neuroscience Training GrantR25NS065723 · NINDS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI CARMICHAEL, STANLEY THOMAS · 2009 to 2023
$2.8MNovel Strategies and Mechanisms to Target APOE and Alzheimer's DiseaseR01AG047644 · NIA · WASHINGTON UNIVERSITY · PI HOLTZMAN, DAVID M. · 2014 to 2018
$2.8MExamining the role of adaptive immunity in Alzheimer's Disease pathogenesisRF1AG055524 · NIA · UNIVERSITY OF CALIFORNIA-IRVINE · PI BLURTON-JONES, MATHEW MARK · 2017 to 2017
$2.7MA novel platform for the investigation of human microgliaRF1DA048813 · NIDA · UNIVERSITY OF CALIFORNIA-IRVINE · PI BLURTON-JONES, MATHEW MARK, GANDHI, SUNIL · 2019 to 2021
$2.1MRole of C9orf72 in NeurodegenerationR01NS097545 · NINDS · CEDARS-SINAI MEDICAL CENTER · PI BALOH, ROBERT · 2016 to 2020
$2.0MManipulating DNA repair enzymes to examine the interactions between aging and Alzheimers disease with iPSC-derived microgliaR01AG056303 · NIA · UNIVERSITY OF CALIFORNIA-IRVINE · PI BLURTON-JONES, MATHEW MARK · 2017 to 2021
$1.9MHoward Hughes Medical InstituteNIA NIH HHS P30 AG066519NIA NIH HHS P50 AG016573NIA NIH HHS R01 AG047644NIA NIH HHS R01 AG056303NIA NIH HHS R01 AG061895NIA NIH HHS RF1 AG047644NIA NIH HHS RF1 AG055524NINDS NIH HHS K08 NS105916NINDS NIH HHS R01 NS085207NINDS NIH HHS R01 NS090934NINDS NIH HHS R01 NS097545NINDS NIH HHS R25 NS065723NINDS NIH HHS RF1 NS090934NINDS NIH HHS UE5 NS065723
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.
Indexed as
AgingAmyloidAnimalsC9orf72 ProteinDisease Models, AnimalDNA Repeat ExpansionLysosomesMiceMice, KnockoutMicrogliaSynapsesAmyloidC9orf72 ProteinAlzheimer’s diseaseamyotrophic lateral sclerosisC9orf72frontotemporal dementiamicroglianeurodegeneration
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