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  2. Zinc induces reactive astrogliosis through ERK-dependent activation of Stat3 and promotes synaptic degeneration

Zinc induces reactive astrogliosis through ERK-dependent activation of Stat3 and promotes synaptic degeneration

  • J Neurochem. 2021 Dec;159(6):1016-1027. doi: 10.1111/jnc.15531.
Zhang Huiliang 1 Yang Mengzhe 1 Wang Xiaochuan 1 Wei Hui 1 2 Du Min 1 Wang Mengqi 1 Wang Jianzhi 1 Chen Zhongshan 2 Peng Caixia 3 4 Liu Rong 1
Affiliations

Affiliations

  • 1 Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Taikang Tongji Hospital, Wuhan, China.
  • 3 Key Laboratory for Molecular Diagnosis of Hubei Province, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4 Central Laboratory, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract

Reactive astrogliosis is an early event in Alzheimer's disease (AD) brain and plays a key role in synaptic degeneration in AD development. Zinc accumulates in extracellular fraction and synaptosomes in AD human brains with its effect on reactive astrocytes remaining unknown. Through Western blotting, Quantitative polymerase chain reaction (qPCR), and immunofluorescence detection on primary astrocytes treated by zinc and/or zinc chelator, we revealed that zinc induced harmful A1-type reactive astrogliosis in cultured primary astrocytes; the latter, promoted synaptic degeneration in primary neurons. The mechanism investigation showed that zinc induced activation of extracellular regulated protein kinase (ERK) and Janus kinase 2 (JAK2), which phosphorylated signal transduction and transcription activator 3 (STAT3) at serine 727 (S727-Stat3) and tyrosine 705 (Y705-Stat3), respectively, resulting in activation of STAT3. STAT3 phosphorylation at S727 by ERK plays a key role in zinc-induced astrogliosis. These data imply a new molecular mechanism of reactive astrogliosis in AD, in which excessive zinc activates STAT3 through up-regulating ERK signaling pathway.

Keywords

Alzheimer's disease; ERK; Stat3; reactive astrogliosis; synaptic degeneration; zinc.

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