Zinc finger protein 335 mediates lipopolysaccharide‐induced neurodegeneration and memory loss as a transcriptional factor in microglia

Author:

Kong Wei1,Xie Zhen1,Shang Xiaokang1,Hayashi Yoshinori2,Lan Fei1,Narengaowa 1,Zhao Shuxuan1,Li Hui1,Quan Zhenzhen1ORCID,Wu Zhou3,Nakanishi Hiroshi4,Qing Hong1,Ni Junjun1ORCID

Affiliation:

1. Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science Beijing Institute of Technology Beijing China

2. Department of Physiology Nihon University School of Dentistry Chiyoda‐ku Tokyo Japan

3. Department of Aging Science and Pharmacology, OBT Research Center, Faculty of Dental Science Kyushu University Fukuoka Japan

4. Department of Pharmacology, Faculty of Pharmacy Yasuda Women's University Hiroshima Japan

Abstract

AbstractZinc finger protein 335 (Zfp335) is a transcription factor that regulates mammalian neurogenesis and neuronal differentiation. It is a causative factor for severe microcephaly, small somatic size, and neonatal death. Here, we evaluated the effects of Zfp335 in the adult mouse brain after lipopolysaccharide (LPS) challenge. We used wild‐type (WT) and Zfp335 knock‐down (Zfp335+/−) mice with LPS administered in the intracerebral ventricle in vivo and cultured microglia treated with LPS in vitro. The impact of Zfp335 was evaluated by RT‐PCR, RNA‐sequencing, western blotting, immunocytochemistry, ELISA, and the memory behavior tests. Knockdown of Zfp335 expression ameliorated microglia activation significantly, including reduced mRNA and protein expression of Iba1, reduced numbers of microglia, reduced cell diameter, and increased branch length, in the brains of 2‐month‐old mice after LPS treatment. Zfp335 was expressed in microglia and neurons, but increased in microglia, not neurons, in the brain of mice after LPS administration. LPS‐induced microglia‐mediated neurodegeneration was dependent upon microglial Zfp335 controlled by nuclear factor‐kappa B. Microglial Zfp335 affected neuronal activity through transcriptional regulation of lymphocyte antigen‐6M (Ly6M). Our data suggest that Zfp335 is a key transcription factor that exacerbates microglia‐mediated neurodegeneration through upregulation of Ly6M expression. Inhibition of microglial Zfp335 may be a new strategy for preventing brain disease induced by microglia activation.

Funder

Beijing Natural Science Foundation

National Natural Science Foundation of China

Publisher

Wiley

Subject

Cellular and Molecular Neuroscience,Neurology

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