L1CAM Beneficially Inhibits Histone Deacetylase 2 Expression under Conditions of Alzheimer’s Disease

Author(s): Chengliang Hu, Junkai Hu, Xianghe Meng, Hongli Zhang, Huifan Shen, Peizhi Huang, Melitta Schachner*, Weijiang Zhao*.

Journal Name: Current Alzheimer Research

Volume 17 , Issue 4 , 2020

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Abstract:

Background: Cognitive capacities in Alzheimer’s Disease (AD) are impaired by an epigenetic blockade mediated by histone deacetylase 2 (HDAC2), which prevents the transcription of genes that are important for synaptic plasticity.

Objective: Investigation of the functional relationship between cell adhesion molecule L1 and HDAC2 in AD.

Methods: Cultures of dissociated cortical and hippocampal neurons from wild-type or L1-deficient mice were treated with Aβ1-42 for 24 h. After removal of Aβ1-42 cells were treated with the recombinant L1 extracellular domain (rL1) for 24 h followed by immunohistochemistry, western blotting, and reverse transcription PCR to evaluate the interaction between L1 and HDAC2.

Results: Aβ and HDAC2 protein levels were increased in APPSWE/L1+/- mutant brains compared to APPSWE mutant brains. Administration of the recombinant extracellular domain of L1 to cultured cortical and hippocampal neurons reduced HDAC2 mRNA and protein levels. In parallel, reduced phosphorylation levels of glucocorticoid receptor 1 (GR1), which is implicated in regulating HDAC2 levels, was observed in response to L1 administration. Application of a glucocorticoid receptor inhibitor reduced Aβ-induced GR1 phosphorylation and prevented the increase in HDAC2 levels. HDAC2 protein levels were increased in cultured cortical neurons from L1-deficient mice. This change could be reversed by the administration of the recombinant extracellular domain of L1.

Conclusion: Our results suggest that some functionally interdependent activities of L1 and HDAC2 contribute to ameliorating the phenotype of AD by GR1 dephosphorylation, which leads to reduced HDAC2 expression. The combined findings encourage further investigations on the beneficial effects of L1 in the treatment of AD.

Keywords: Alzheimer's disease, cell adhesion molecule L1, histone deacetylase 2, glucocorticoid receptor 1, brain, neuron.

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Article Details

VOLUME: 17
ISSUE: 4
Year: 2020
Page: [382 - 392]
Pages: 11
DOI: 10.2174/1567205017666200422155323
Price: $65

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