Original Article
High Aβ load may cause microglial cell dysfunction and reduced nuclear repressor element-1 silencing transcription factor (REST) expression which might be ascribed to its degradation by ubiquitination
Abstract
Background: This study aimed to investigate the effects of high Aβ load on the microglial function, neuronal activity, and repressor element-1 silencing transcription factor (REST) expression and nuclear localization and further explore the mechanism underlying nuclear REST deficiency and the correlation between pathology and symptoms in Alzheimer’s disease (AD).
Methods: BV2 cells and N2A cells were treated with Aβ at different concentrations, and the viability, apoptosis and autophagy of these cells were further evaluated. The expression of major histocompatibility complex class II (MHC-II, a marker of microglial activation), REST in the neurons and REST specific phosphorylase casein kinase 1 (CK1) were detected.
Results: Aβ at a low concentration (2.5 µmol/L) could alter the microglial morphology, and the proportion of amoebic microglia and protein expression of MHC-II increased in a Aβ concentration dependent manner. Aβ at a high concentration (10 µmol/L) was able to reduce REST expression, elevate the expression of pro-apoptotic and pro-autophagic genes, inhibit the expression of anti-apoptotic gene, and reduce the neuronal activity. REST expression reduced, but CK1 increased in neurons, and CK1 inhibitor significantly increased REST expression. there was co-expression of REST and CK1 in the brain of AD mice, which was characterized by reduced nuclear REST expression and elevated CK1 expression.
Conclusions: High Aβ load may cause microglial cell dysfunction and loss of REST expression in the neurons, resulting in dementia. The reduced nuclear REST might be ascribed to its degradation by ubiquitination. This supports the hypothesis that high plaque load may increase the risk for dementia.
Methods: BV2 cells and N2A cells were treated with Aβ at different concentrations, and the viability, apoptosis and autophagy of these cells were further evaluated. The expression of major histocompatibility complex class II (MHC-II, a marker of microglial activation), REST in the neurons and REST specific phosphorylase casein kinase 1 (CK1) were detected.
Results: Aβ at a low concentration (2.5 µmol/L) could alter the microglial morphology, and the proportion of amoebic microglia and protein expression of MHC-II increased in a Aβ concentration dependent manner. Aβ at a high concentration (10 µmol/L) was able to reduce REST expression, elevate the expression of pro-apoptotic and pro-autophagic genes, inhibit the expression of anti-apoptotic gene, and reduce the neuronal activity. REST expression reduced, but CK1 increased in neurons, and CK1 inhibitor significantly increased REST expression. there was co-expression of REST and CK1 in the brain of AD mice, which was characterized by reduced nuclear REST expression and elevated CK1 expression.
Conclusions: High Aβ load may cause microglial cell dysfunction and loss of REST expression in the neurons, resulting in dementia. The reduced nuclear REST might be ascribed to its degradation by ubiquitination. This supports the hypothesis that high plaque load may increase the risk for dementia.
