TY - JOUR
T1 - C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation
AU - Lall, Deepti
AU - Lorenzini, Ileana
AU - Mota, Thomas A.
AU - Bell, Shaughn
AU - Mahan, Thomas E.
AU - Ulrich, Jason D.
AU - Davtyan, Hayk
AU - Rexach, Jessica E.
AU - Muhammad, A. K.M.Ghulam
AU - Shelest, Oksana
AU - Landeros, Jesse
AU - Vazquez, Michael
AU - Kim, Junwon
AU - Ghaffari, Layla
AU - O'Rourke, Jacqueline Gire
AU - Geschwind, Daniel H.
AU - Blurton-Jones, Mathew
AU - Holtzman, David M.
AU - Sattler, Rita
AU - Baloh, Robert H.
N1 - Funding Information:
We thank the Cedars-Sinai Applied Genomics, Computation & Translational Core for RNA-seq, the Cedars-Sinai Animal Behavior Core for mice behavior experiments, Dr. Michael Workman and Dr. Ritchie Ho for help with RNA-seq analysis, and all members of the Baloh and Sattler laboratory for helpful discussions. This work was supported by NIH grant NS097545 (R.H.B.), the Robert and Louise Schwab family (R.H.B.), the Cedars-Sinai ALS Research Fund (R.H.B.), NIH grants NS090934 (D.M.H.) and AG047644 (D.M.H.), the JPB Foundation (D.M.H.), NIH grant RO1NS085207 (R.S.), the Muscular Dystrophy Association (R.S.), the ALS Association (R.S.), the Robert Packard Center for ALS Research (R.S.), the Barrow Neurological Foundation (R.S.), the Rainwater Charitable Foundation (D.H.G.), NIH grant 5R25 NS065723 (J.E.R.), and NIH grants AG055524 (M.B.-J.) and AG061895 (H.D.). T.A.M. is supported by the Howard Hughes Medical Institute through the James H. Gilliam Fellowships for Advanced Study program. D.L. and R.H.B. conceived and planned the study. D.L. coordinated the project and was involved in all experiments, imaging, data collection, quantification, and statistical analysis. I.L. J.K. L.G. and R.S. were involved in synaptic analysis. T.E.M. J.D.U. and D.M.H. provided reagents and performed Aβ-ELISA studies and data analysis. H.D. and M.B.-J. were involved in mouse IgG, B, and T cell experiments. J.E.R. and D.H.G. performed WGCNA analysis and bioinformatics. D.L. A.K.M.G.M. and T.A.M. performed tissue collection and histologic analysis. J.G.O. did western blotting for microglia and STING. D.L. and A.K.M.G.M. performed immunohistochemistry. M.V. and J.L. established and maintained mouse colonies. D.L. T.A.M. and S.B. performed scRNA-seq and bulk RNA-seq. D.L. S.B. and R.H.B. performed scRNA-seq and RNA-seq analyses. D.L. R.S. and R.H.B. wrote the manuscript with input from all authors. 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. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. One or more of the authors of this paper received support from a program designed to increase minority representation in science. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.
Funding Information:
We thank the Cedars-Sinai Applied Genomics, Computation & Translational Core for RNA-seq, the Cedars-Sinai Animal Behavior Core for mice behavior experiments, Dr. Michael Workman and Dr. Ritchie Ho for help with RNA-seq analysis, and all members of the Baloh and Sattler laboratory for helpful discussions. This work was supported by NIH grant NS097545 (R.H.B.), the Robert and Louise Schwab family (R.H.B.), the Cedars-Sinai ALS Research Fund (R.H.B.), NIH grants NS090934 (D.M.H.) and AG047644 (D.M.H.), the JPB Foundation (D.M.H.), NIH grant RO1NS085207 (R.S.), the Muscular Dystrophy Association (R.S.), the ALS Association (R.S.), the Robert Packard Center for ALS Research (R.S.), the Barrow Neurological Foundation (R.S.), the Rainwater Charitable Foundation (D.H.G.), NIH grant 5R25 NS065723 (J.E.R.), and NIH grants AG055524 (M.B.-J.) and AG061895 (H.D.). T.A.M. is supported by the Howard Hughes Medical Institute through the James H. Gilliam Fellowships for Advanced Study program.
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/7/21
Y1 - 2021/7/21
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - C9orf72
KW - amyotrophic lateral sclerosis
KW - frontotemporal dementia
KW - microglia
KW - neurodegeneration
UR - http://www.scopus.com/inward/record.url?scp=85110332071&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2021.05.020
DO - 10.1016/j.neuron.2021.05.020
M3 - Article
C2 - 34133945
AN - SCOPUS:85110332071
SN - 0896-6273
VL - 109
SP - 2275-2291.e8
JO - Neuron
JF - Neuron
IS - 14
ER -