Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model.

Autor:	Carling GK; Helen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA; Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10065, USA., Fan L; Helen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA., Foxe NR; Helen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA; Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10065, USA., Norman K; Helen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA., Wong MY; Helen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA., Zhu D; Helen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA., Corona C; Burke Neurological Institute, Weill Cornell Medicine, White Plains, NY 10605, USA., Razzoli A; Transfusion Medicine Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia 42122, Italy; Clinical and Experimental PhD Program, University of Modena and Reggio Emilia, Modena 41121, Italy., Yu F; Helen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA., Yarahmady A; Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada., Ye P; Helen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA., Chen H; Helen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA., Huang Y; Helen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA; Biochemistry, Structural Biology, Cell Biology, Developmental Biology, and Molecular Biology Graduate Program, Weill Cornell Medicine, New York, NY 10065, USA., Amin S; Helen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA., Sereda R; Department of Developmental and Molecular Biology, Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA., Lopez-Lee C; Helen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA; Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10065, USA., Zacharioudakis E; Department of Biochemistry, Department of Medicine, Montefiore Einstein Comprehensive Cancer Center, Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA., Chen X; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA., Xu J; Cleveland Clinic Genome Center and Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA., Cheng F; Cleveland Clinic Genome Center and Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA., Gavathiotis E; Department of Biochemistry, Department of Medicine, Montefiore Einstein Comprehensive Cancer Center, Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA., Cuervo AM; Department of Developmental and Molecular Biology, Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA., Holtzman DM; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA., Mok SA; Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada., Sinha SC; Helen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA., Sidoli S; Department of Biochemistry, Department of Medicine, Montefiore Einstein Comprehensive Cancer Center, Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA., Ratan RR; Burke Neurological Institute, Weill Cornell Medicine, White Plains, NY 10605, USA., Luo W; Helen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA., Gong S; Helen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA., Gan L; Helen and Robert Appel Alzheimer's Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: lig2033@med.cornell.edu.
Jazyk:	angličtina
Zdroj:	Neuron [Neuron] 2024 Dec 04; Vol. 112 (23), pp. 3877-3896.e8. Date of Electronic Publication: 2024 Sep 30.
DOI:	10.1016/j.neuron.2024.09.006
Abstrakt:	The strongest risk factors for late-onset sporadic Alzheimer's disease (AD) include the ε4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2 R47H (R47H) in female P301S tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting detrimental disease mechanisms. We find that R47H induces neurodegeneration in 9- to 10-month-old female APOE4 tauopathy mice. The combination of APOE4 and R47H (APOE4-R47H) worsened hyperphosphorylated tau pathology in the frontal cortex and amplified tauopathy-induced microglial cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling and downstream interferon response. APOE4-R47H microglia displayed cGAS- and BAX-dependent upregulation of senescence, showing association between neurotoxic signatures and implicating mitochondrial permeabilization in pathogenesis. By uncovering pathways enhanced by the strongest AD risk factors, our study points to cGAS-STING signaling and associated microglial senescence as potential drivers of AD risk. Competing Interests: Declaration of interests L.G. is founder and equity holder of Aeton Therapeutics, Inc. S.C.S. is an equity holder and a consultant of Aeton Therapeutics, Inc. L.G. is scientific co-founder of Neurovanda and consults for Retro Biosciences. D.M.H. is 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. D.M.H. is on the scientific advisory board of Denali, Genentech, and Cajal Neuroscience and consults for Asteroid. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu