Pax6/c-Myb regulates neuronal apoptosis in a mouse model of Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is the most frequent neurodegenerative disorder which

is characterized by impaired mental functions such as memory, language,

perception, behavior and personality, as well as cognitive skills. The molecular

mechanisms underlying this disease is still largely unknown, but numerous

evidence emerge to support a cell cycle hypothesis which implicates the

deregulation of cell cycle proteins as key mediators of neuronal dysfunction and

loss in AD brains. One of these signals in Aβ-induced neuronal death model is

Cdk/Rb/E2F pathway, where Aβ insult evokes activation of Cdk4/6, which

subsequently phosphorylates pRb protein, resulting in activation of E2F

transcription factors. However, the mechanism(s) by which Cdk/Rb/E2F mediates

neuronal death remains elusive. Therefore, the goal of this project is to

characterize the downstream events of cell cycle pathway, which include the

involvement of transcription factors c-Myb, Pax6 and Patz1 in Aβ-induced

neuronal death signaling. In this study, we showed that Pax6 is a direct target gene

for Both E2F1 and c-Myb. Both Pax6 and c-Myb are up-regulated by Aβ insults in

cultured cortical neurons. And with E2F1 silencing by siRNA, Aβ-induced Pax6

and c-Myb expression is blocked, suggesting E2F1 is responsible for their

elevation. Importantly, siRNA-mediated downregulation of either c-Myb or Pax6

protects neurons from death evoked by Aβ peptide, suggesting they are proapoptotic

proteins, delivering death signals sent from upstream E2F1. Next,

though ChIP assay, we identified two target genes for Pax6. One is Patz1, another

transcription factor that is Aβ-induced pro-apoptotic protein. The other one is

GSK3β, which is a pathogenic kinase involved in Tau protein

hyperphosphorylation and NFT formation. In conclusion, this dissertation shows

that cell cycle regulators Cdk/Rb/E2F modulate neuronal death signals by

activating downstream transcription factors c-Myb and Pax6, further upregulating

GSK3β. We provided evidence suggesting that Aβ induced neurotoxicity leads to

Tau hyperphosphorylation through a mechanism involving cell cycle activation

and subsequent activation of c-Myb/Pax6/GSK3β. In brief, in the present study,

we delineate a transcriptional cascade downstream of cell cycle pathway leads to

neuronal apoptosis as well as Tau/NFT pathology. The characterization of this

novel pathway lends support for development of new therapeutic agents and for

better experimental models for AD. Lastly, the cascade between cell cycle

activation and tauopathy in Aβ-induced neuronal death needs to be further

researched in the future.