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Activation of FAK/Rac1/Cdc42-GTPase signaling ameliorates impaired microglial migration response to Aβ42 in triggering receptor expressed on myeloid cells 2 loss-of-function murine models.
FASEB J. 2020 Jul 01 [Online ahead of print]FJ

Abstract

Mutation of Triggering receptor expressed on myeloid cells 2 (TREM2) impairs the response of microglia to amyloid-β (Aβ) pathology in Alzheimer's disease (AD), although the mechanism governing TREM2-regulated microglia recruitment to Aβ plaques remains unresolved. Here, we confirm that TREM2 mutation attenuates microglial migration. Then, using Trem2-/- mice and an R47H variant mouse model for AD generated for this study, we show that TREM2 deficiency or the AD-associated R47H mutation results in inhibition of FAK and Rac1/Cdc42-GTPase signaling critical for cell migration. Intriguingly, treatment with CN04, a Rac1/Cdc42-GTPase activator, partially enhances microglial migration in response to oligomeric Aβ42 in Trem2-/- or R47H microglia both in vitro and in vivo. Our study shows that the dysfunction of microglial migration in the AD-associated TREM2 R47H variant is caused by FAK/Rac1/Cdc42 signaling disruption, and that activation of this signaling ameliorates impaired microglial migration response to Aβ42 , suggesting a therapeutic target for R47H-bearing patients with high risk of AD.

Authors+Show Affiliations

Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China.Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China.Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China.Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China.Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China.Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China.Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China. Shenzhen Research Institute, Xiamen University, Shenzhen, China.Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China.Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China.Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen, China.Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China. State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, China.Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China.Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China. Shenzhen Research Institute, Xiamen University, Shenzhen, China. Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32613609

Citation

Rong, Zhouyi, et al. "Activation of FAK/Rac1/Cdc42-GTPase Signaling Ameliorates Impaired Microglial Migration Response to Aβ42 in Triggering Receptor Expressed On Myeloid Cells 2 Loss-of-function Murine Models." FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 2020.
Rong Z, Cheng B, Zhong L, et al. Activation of FAK/Rac1/Cdc42-GTPase signaling ameliorates impaired microglial migration response to Aβ42 in triggering receptor expressed on myeloid cells 2 loss-of-function murine models. FASEB J. 2020.
Rong, Z., Cheng, B., Zhong, L., Ye, X., Li, X., Jia, L., Li, Y., Shue, F., Wang, N., Cheng, Y., Huang, X., Liu, C. C., Fryer, J. D., Wang, X., Zhang, Y. W., & Zheng, H. (2020). Activation of FAK/Rac1/Cdc42-GTPase signaling ameliorates impaired microglial migration response to Aβ42 in triggering receptor expressed on myeloid cells 2 loss-of-function murine models. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. https://doi.org/10.1096/fj.202000550RR
Rong Z, et al. Activation of FAK/Rac1/Cdc42-GTPase Signaling Ameliorates Impaired Microglial Migration Response to Aβ42 in Triggering Receptor Expressed On Myeloid Cells 2 Loss-of-function Murine Models. FASEB J. 2020 Jul 1; PubMed PMID: 32613609.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of FAK/Rac1/Cdc42-GTPase signaling ameliorates impaired microglial migration response to Aβ42 in triggering receptor expressed on myeloid cells 2 loss-of-function murine models. AU - Rong,Zhouyi, AU - Cheng,Baoying, AU - Zhong,Li, AU - Ye,Xiaowen, AU - Li,Xin, AU - Jia,Lin, AU - Li,Yanfang, AU - Shue,Francis, AU - Wang,Na, AU - Cheng,Yiyun, AU - Huang,Xiaohua, AU - Liu,Chia-Chen, AU - Fryer,John D, AU - Wang,Xin, AU - Zhang,Yun-Wu, AU - Zheng,Honghua, Y1 - 2020/07/01/ PY - 2020/03/08/received PY - 2020/06/02/revised PY - 2020/06/08/accepted PY - 2020/7/3/entrez KW - Alzheimer's disease KW - FAK/Rac1/Cdc42 pathway KW - TREM2 KW - microglia KW - migration JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JO - FASEB J. N2 - Mutation of Triggering receptor expressed on myeloid cells 2 (TREM2) impairs the response of microglia to amyloid-β (Aβ) pathology in Alzheimer's disease (AD), although the mechanism governing TREM2-regulated microglia recruitment to Aβ plaques remains unresolved. Here, we confirm that TREM2 mutation attenuates microglial migration. Then, using Trem2-/- mice and an R47H variant mouse model for AD generated for this study, we show that TREM2 deficiency or the AD-associated R47H mutation results in inhibition of FAK and Rac1/Cdc42-GTPase signaling critical for cell migration. Intriguingly, treatment with CN04, a Rac1/Cdc42-GTPase activator, partially enhances microglial migration in response to oligomeric Aβ42 in Trem2-/- or R47H microglia both in vitro and in vivo. Our study shows that the dysfunction of microglial migration in the AD-associated TREM2 R47H variant is caused by FAK/Rac1/Cdc42 signaling disruption, and that activation of this signaling ameliorates impaired microglial migration response to Aβ42 , suggesting a therapeutic target for R47H-bearing patients with high risk of AD. SN - 1530-6860 UR - https://www.unboundmedicine.com/medline/citation/32613609/Activation_of_FAK/Rac1/Cdc42-GTPase_signaling_ameliorates_impaired_microglial_migration_response_to_Aβ42_in_triggering_receptor_expressed_on_myeloid_cells_2_loss-of-function_murine_models L2 - https://doi.org/10.1096/fj.202000550RR DB - PRIME DP - Unbound Medicine ER -
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