Affiliation:
1. Center for Neuroscience, Shantou University Medical College, 22 Xin Ling Road, Shantou, Guangdong 515041, China
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.
Funder
Li Ka Shing Foundation
National Natural Science Foundation of China
Publisher
Bentham Science Publishers Ltd.
Subject
Neurology (clinical),Neurology
Cited by
3 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献