Induction of Ketosis May Improve Mitochondrial Function and Decrease Steady-State Amyloid-Beta Precursor Protein (APP) Levels in the Aged Dog

Brain Res. 2008 Aug 21;1226:209-17. doi: 10.1016/j.brainres.2008.06.005. Epub 2008 Jun 11.

Abstract

Region specific declines in the cerebral glucose metabolism are an early and progressive feature of Alzheimer's disease (AD). Such declines occur pre-symptomatically and offer a potential point of intervention in developing AD therapeutics. Medium chain triglycerides (MCTs), which are rapidly converted to ketone bodies, were tested for their ability to provide an alternate energy source to neurons suffering from compromised glucose metabolism. The present study determined the short-term effects of ketosis in aged dogs, a natural model of amyloidosis. The animals were administered a 2 g/kg/day dose of MCTs for 2 months. Mitochondrial function and oxidative damage assays were then conducted on the frontal and parietal lobes. Amyloid-beta (Abeta), amyloid precursor protein (APP) processing and beta-site APP cleaving enzyme (BACE1) assays were conducted on the frontal, parietal and occipital lobes. Aged dogs receiving MCTs, as compared to age-matched controls, showed dramatically improved mitochondrial function, as evidenced by increased active respiration rates. This effect was most prominent in the parietal lobe. The improved mitochondrial function may have been due to a decrease in oxidative damage, which was limited to the mitochondrial fraction. Steady-state APP levels were also decreased in the parietal lobe after short-term MCT administration. Finally, there was a trend towards a decrease in total Abeta levels in the parietal lobe. BACE1 levels remained unchanged. Combined, these findings suggest that short-term MCT administration improves energy metabolism and decreases APP levels in the aged dog brain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxybutyric Acid / blood
  • Aging*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Dogs
  • Female
  • Frontal Lobe / drug effects
  • Frontal Lobe / metabolism
  • Frontal Lobe / physiopathology
  • Ketosis / chemically induced
  • Ketosis / pathology
  • Ketosis / physiopathology*
  • Lipid Peroxidation / drug effects
  • Male
  • Mitochondria / drug effects
  • Mitochondria / physiology*
  • Models, Biological
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Parietal Lobe / drug effects
  • Parietal Lobe / metabolism
  • Parietal Lobe / physiopathology
  • Time Factors
  • Triglycerides / administration & dosage*

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Triglycerides
  • Amyloid Precursor Protein Secretases
  • 3-Hydroxybutyric Acid