Induction of ketosis may improve mitochondrial function and decrease steady-state amyloid-β precursor protein (APP) levels in the aged dog

Christa M. Studzinski, William A. MacKay, Tina L. Beckett, Samuel T. Henderson, M. Paul Murphy, Patrick G. Sullivan, W. Mc Intyre Burnham

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

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-β (Aβ), amyloid precursor protein (APP) processing and β-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 Aβ 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.

Original languageEnglish
Pages (from-to)209-217
Number of pages9
JournalBrain Research
Volume1226
DOIs
StatePublished - Aug 21 2008

Bibliographical note

Funding Information:
This project was funded by CanCog Technologies Inc., an NSERC scholarship to CMS and by NCRR grant P20 RR020171 to MPM. The investigators adhered to the “Guide for the Care and Use of Laboratory Animals” prepared by the Committee on Care and Use of Laboratory Animals of the Laboratory Animal Resources, National Research Council (NIH Publication No 86–23, Revised 1985). We thank Accera Inc. for providing the MCTs and Robin Webb for her assistance with the BACE blots. We thank the animal technicians and research technicians for their help with the study. Parts of this manuscript were obtained from the first author's Ph.D. dissertation.

Keywords

  • Alzheimer's disease
  • Amyloid precursor protein
  • Amyloid-β
  • Dog
  • Energy metabolism
  • Ketone
  • Mitochondria

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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