Ketones block amyloid entry and improve cognition in an Alzheimer's model

Neurobiol Aging. 2016 Mar;39:25-37. doi: 10.1016/j.neurobiolaging.2015.11.018. Epub 2015 Dec 7.

Abstract

Sporadic Alzheimer's disease (AD) is responsible for 60%-80% of dementia cases, and the most opportune time for preventive intervention is in the earliest stage of its preclinical phase. As traditional mitochondrial energy substrates, ketone bodies (ketones, for short), beta-hydroxybutyrate, and acetoacetate, have been reported to provide symptomatic improvement and disease-modifying activity in epilepsy and neurodegenerative disorders. Recently, ketones are thought as more than just metabolites and also as endogenous factors protecting against AD. In this study, we discovered a novel neuroprotective mechanism of ketones in which they blocked amyloid-β 42, a pathologic hallmark protein of AD, entry into neurons. The suppression of intracellular amyloid-β 42 accumulation rescued mitochondrial complex I activity, reduced oxidative stress, and improved synaptic plasticity. Most importantly, we show that peripheral administration of ketones significantly reduced amyloid burden and greatly improved learning and memory ability in a symptomatic mouse model of AD. These observations provide us insights to understand and to establish a novel therapeutic use of ketones in AD prevention.

Keywords: Acetoacetate; Alzheimer's disease; Ketones; Mitochondria; β-hydroxybutyrate.

Publication types

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

MeSH terms

  • 3-Hydroxybutyric Acid / pharmacology
  • 3-Hydroxybutyric Acid / therapeutic use
  • Acetoacetates / pharmacology
  • Acetoacetates / therapeutic use
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / prevention & control
  • Alzheimer Disease / psychology*
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Cognition / drug effects*
  • Depression, Chemical
  • Disease Models, Animal
  • Ketone Bodies / pharmacology*
  • Ketone Bodies / therapeutic use*
  • Learning / drug effects
  • Memory / drug effects
  • Mice, Transgenic
  • NADH Dehydrogenase / metabolism
  • Neuronal Plasticity / drug effects
  • Neurons / metabolism
  • Neuroprotective Agents*
  • Oxidative Stress / drug effects
  • Peptide Fragments / metabolism*
  • Stimulation, Chemical

Substances

  • Acetoacetates
  • Amyloid beta-Peptides
  • Ketone Bodies
  • Neuroprotective Agents
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • acetoacetic acid
  • NADH Dehydrogenase
  • 3-Hydroxybutyric Acid