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

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

Author information

1
Department of Neurology, Barrow Neurological Institute, St. Joseph Hospital and Medical Center, Phoenix, AZ, USA.
2
Department of Biological Chemistry, Molecular Biology Institute, Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, University of California, Los Angeles, CA, USA.
3
Division of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
4
The Pasarow Mass Spectrometry Laboratory, NPI-Semel Institute, David Geffen School of Medicine and Brain Research Institute, David Geffen School of medicine, University of California, Los Angeles, CA, USA.
5
Banner Alzheimer's Institute, Phoenix, AZ, USA.
6
Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. Electronic address: felixs@ucla.edu.
7
Department of Neurology, Barrow Neurological Institute, St. Joseph Hospital and Medical Center, Phoenix, AZ, USA. Electronic address: jiong.shi@dignityhealth.org.

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

[Indexed for MEDLINE]

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