Sting and p53 DNA repair pathways are compromised in Alzheimer's disease

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Alzheimer's disease (AD) is the leading cause of dementia, characterized by DNA damage in neurons.
• Neurons, being post-mitotic, have limited repair mechanisms for hazardous double-strand DNA breaks (DSBs).
• The role of increased DNA damage versus impaired DNA repair in AD pathogenesis is unclear.

Purpose of the Study:

• To investigate the status of p53 oligomerization and DNA repair pathways in Alzheimer's disease.
• To determine if oxidative stress contributes to DNA damage and repair deficits in AD.
• To explore the implications of impaired DNA repair signaling in AD progression.

Main Methods:

• Analyzed p53 monomer:dimer ratio in temporal lobes of AD patients and controls.
• Utilized in vitro oxidation of p53 and COMET assay to assess DNA damage and repair.
• Measured levels of DNA repair proteins (14-3-3σ, γ-H2AX, ATM) and oxidative stress markers (protein carbonylation).
• Investigated cGAS-STING-interferon signaling pathway activation in response to DSBs.

Main Results:

• Increased monomer:dimer ratio of phosphorylated p53 in AD brains indicates compromised oligomerization.
• Elevated DNA degradation (COMET test) and protein carbonylation suggest increased oxidative stress and DNA damage/repair inhibition.
• Upregulation of DNA repair markers (γ-H2AX, ATM) and support proteins (14-3-3σ) observed.
• Impaired cGAS-STING-interferon signaling with STING depletion and lack of interferon response despite DSBs.

Conclusions:

• Oxidative stress may impair the DNA damage response (DDR) by altering p53 oligomerization, hindering DSB repair in AD.
• Failure of immune-stimulated DNA repair pathways contributes to neuronal loss in Alzheimer's disease.
• Targeting p53 oligomerization and DNA repair mechanisms presents potential therapeutic strategies for AD.