Early growth response‐1 regulates acetylcholinesterase and its relation with the course of Alzheimer’s disease

Abstract

Our previous studies showed that the transcription factor early growth response‐1 (EGR1) may play a role in keeping the brain cholinergic function intact in the preclinical stages of Alzheimer’s disease (AD). In order to elucidate the mechanisms involved, we first performed data mining on our previous microarray study on postmortem human prefrontal cortex (PFC) for the changes in the expression of EGR1 and acetylcholinesterase (AChE) and the relationship between them during the course of AD. The study contained 49 patients, ranging from non‐demented controls (Braak stage 0) to late AD patients (Braak stage VI). We found EGR1‐mRNA was high in early AD and decreased in late AD stages, while AChE‐mRNA was stable in preclinical AD and slightly decreased in late AD stages. A significant positive correlation was found between the mRNA levels of these two molecules. In addition, we studied the relationship between EGR1 and AChE mRNA levels in the frontal cortex of 3–12‐months old triple‐transgenic AD (3xTg‐AD) mice. EGR1‐ and AChE‐mRNA were lower in 3xTg‐AD mice compared with wild‐type (WT) mice. A significant positive correlation between these two molecules was present in the entire group and in each age group of either WT or 3xTg‐AD mice. Subsequently, AChE expression was determined following up‐ or down‐regulating EGR1 in cell lines and the EGR1 levels were found to regulate AChE at both the mRNA and protein levels. Dual‐luciferase assay and electrophoretic mobility shift assay in the EGR1‐overexpressing cells were performed to determine the functionally effective binding sites of the EGR1 on the AChE gene promoter. We conclude that the EGR1 can upregulate AChE expression by a direct effect on its gene promoter, which may contribute significantly to the changes in cholinergic function in the course of AD. The 3xTg‐AD mouse model only reflects later stage AD.

Interference With Complex IV as a Model of Age-Related Decline in Synaptic Connectivity

“…For Egr1, decreased expression has been reported in aged animals and models of AD correlating with associated deficits in synaptic plasticity (Koldamova et al, 2014;Penner et al, 2016). Also, analysis of post-mortem brain tissue from non-demented controls and individuals with AD revealed changes in Egr1 expression corresponding with disease progression (Hu et al, 2019). Interference with Myo6 function, necessary for proper postsynaptic AMPA receptor trafficking, was shown to reduce synaptic numbers and impair AMPA receptor recruitment to postsynaptic sites (Wu et al, 2002;Osterweil et al, 2005;Nash et al, 2010).…”

Key Disease Mechanisms Linked to Alzheimer’s Disease in the Entorhinal Cortex

“…Acetylcholine is the primary neurotransmitter depleted in AD. EGR1 levels modulate acetylcholinesterase mRNA and protein, suggesting EGR1 may significantly contribute to the changes in acetylcholine signaling seen in AD [86]. Furthermore, EGR1, through its action on miRNA-132, was found to modulate the nucleus basalis of Meynert, an area rich in acetylcholine [87].…”

The proto-oncogene DEK regulates neuronal excitability and tau accumulation in Alzheimer’s disease vulnerable neurons

“…We find that one of the most striking effects of Dek silencing is on IEG expression, reminiscent of links between IEGs (e.g. Npas4 and Egr1) and AD pathogenesis (Bartolotti, Segura, & Lazarov, 2016; Castillo et al, 2017; Hu et al, 2019; Miyashita et al, 2014). Somewhat paradoxically, while under basal conditions Dek silencing is accompanied by decreased expression of IEGs, Dek -silenced neurons show a higher induction of these same genes by KCl.…”

“…While uncontestable that reactive microglia and tau accumulation are manifestations of AD, the idea that alterations in network excitability and defects in synaptic homeostasis could also play a role in early disease is gaining traction. Dysregulation of IEGs, like Npas4 and Egr1, has also been linked to AD pathogenesis (Bartolotti, Segura, & Lazarov, 2016; Castillo et al, 2017; Hu et al, 2019; Miyashita et al, 2014) (Frere & Slutsky, 2018; Styr & Slutsky, 2018). Here we uncover DEK as a plausible upstream regulator of all these processes, interconnecting them in a sequence of events that could potentially culminate in the degeneration of ECII neurons during the early stages of AD.…”