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The Carnitine Palmitoyl-Transferase 2 Cascade Hypothesis for Alzheimer's Disease

Hiskias G Keizer1,2, Ruud Brands1,2,3, Ronald S Oosting1,2

  • 1Alloksys Biotechnology, Wageningen, The Netherlands.

Journal of Alzheimer'S Disease : JAD
|December 25, 2023
PubMed

Insights

This study identifies carnitine palmitoyl transferase-2 (CPT2) as a key target in Alzheimer's disease (AD) etiology. Oxidative stress inhibits CPT2, potentially explaining AD's development and offering new therapeutic avenues.

Area of Science:

  • Biochemistry
  • Neuroscience
  • Mitochondrial Biology

Background:

  • The exact cause of Alzheimer's disease (AD) is still unknown despite extensive research.
  • Major AD risk factors converge on producing excess hydrogen peroxide at the inner mitochondrial membrane.

Purpose of the Study:

  • To propose carnitine palmitoyl transferase-2 (CPT2) as a central target in Alzheimer's disease (AD) etiology.
  • To elucidate the mechanism by which CPT2 inhibition contributes to AD pathogenesis.

Main Methods:

  • Hypothesis-driven analysis of CPT2's role in mitochondrial beta-oxidation.
  • Examination of CPT2's sensitivity to hydrogen peroxide.
  • Correlation of CPT2 inhibition with AD risk factors and disease phenotype.

Main Results:

  • CPT2, an inner mitochondrial membrane enzyme crucial for fatty acid beta-oxidation, is highly sensitive to hydrogen peroxide.
  • Excess hydrogen peroxide, generated by AD risk factors, inhibits CPT2 activity.
  • Inhibition of CPT2 leads to the characteristic pathological features observed in Alzheimer's disease.

Conclusions:

  • CPT2 is identified as a pivotal enzyme in the etiology of Alzheimer's disease.
  • Oxidative stress-induced CPT2 inhibition provides a unifying mechanism for AD pathogenesis.
  • This understanding opens immediate possibilities for developing novel AD therapies targeting CPT2.
Keywords:
AMP-kinase pathway dependent integrated stress responseAlzheimer’s diseaseCPT2carnitine palmitoyl transferase 2hydrogen peroxidehypoxialongevityradical oxygen species

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