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Updated: May 13, 2025

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Small molecule DDQ involvement of ERK-mediated signaling pathway with enhanced mitophagy in HT22 cells transfected

Jangampalli Adi Pradeepkiran1, Sudhir Kshirsagar1, Rainier Vladlen Alvir1

  • 1Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.

Biochimica Et Biophysica Acta. Molecular Basis of Disease
|April 13, 2025
PubMed

Insights

Diethyl (3,4-dihydroxy phenethylamine) (quinolin-4-yl) methylphosphonate (DDQ) reduces tau phosphorylation and protects mitochondria in Alzheimer

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Tau hyperphosphorylation is a key pathological hallmark in Alzheimer's disease (AD).
  • Understanding molecular mechanisms underlying tauopathy is crucial for developing effective AD therapeutics.

Purpose of the Study:

  • To investigate the effect of diethyl (3,4-dihydroxy phenethylamine) (quinolin-4-yl) methylphosphonate (DDQ) on tau phosphorylation and mitochondrial function.
  • To explore the potential role of DDQ in mitigating AD-related cellular damage.

Main Methods:

  • HT22 cells were transfected with mTau and treated with DDQ.
  • Western blot analysis was used to detect levels of phosphorylated tau (p-tau) at Ser202 and Thr205, phosphorylated extracellular signal-regulated kinase (p-ERK), LC3B, and TOM20.
  • Mitochondrial protection was assessed in the presence of mTau.

Main Results:

  • DDQ treatment decreased tau phosphorylation at Ser202 and Thr205, and reduced p-ERK levels.
  • DDQ treatment increased levels of LC3B and TOM20, indicating enhanced mitophagy and mitochondrial content.
  • DDQ demonstrated significant mitochondrial protection in mTau-expressing cells.

Conclusions:

  • DDQ inhibits tau and ERK phosphorylation, thereby restoring mitophagy.
  • DDQ's protective effects may involve the Sirt3 activation of the ERK-CREB mediated pathway.
  • DDQ presents a potential therapeutic strategy for Alzheimer's disease by targeting tau pathology and mitochondrial dysfunction.
Keywords:
Alzheimer's diseaseDDQHyperphosphorylationP-ERKP-tau

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