title: Ketones block amyloid entry and improve cognition in an Alzheimer's model.
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.
authors.affiliation: Department of Neurology, Barrow Neurological Institute, St. Joseph Hospital and Medical Center, Phoenix, AZ, USA.
authors.forename: Jun Xiang
authors.initials: JX
authors.lastname: Yin
authors.affiliation: Department of Neurology, Barrow Neurological Institute, St. Joseph Hospital and Medical Center, Phoenix, AZ, USA.
authors.forename: Marwan
authors.initials: M
authors.lastname: Maalouf
authors.affiliation: Department of Neurology, Barrow Neurological Institute, St. Joseph Hospital and Medical Center, Phoenix, AZ, USA.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Han
authors.affiliation: 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.
authors.forename: Minglei
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Division of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Gao
authors.affiliation: Division of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
authors.forename: Turner
authors.initials: T
authors.lastname: Dharshaun
authors.affiliation: 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.
authors.forename: Christopher
authors.initials: C
authors.lastname: Ryan
authors.affiliation: 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.
authors.forename: Julian
authors.initials: J
authors.lastname: Whitelegge
authors.affiliation: Division of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Eisenberg
authors.affiliation: Banner Alzheimer's Institute, Phoenix, AZ, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Reiman
authors.affiliation: Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. Electronic address: felixs@ucla.edu.
authors.forename: Felix E
authors.initials: FE
authors.lastname: Schweizer
authors.affiliation: Department of Neurology, Barrow Neurological Institute, St. Joseph Hospital and Medical Center, Phoenix, AZ, USA. Electronic address: jiong.shi@dignityhealth.org.
authors.forename: Jiong
authors.initials: J
authors.lastname: Shi
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000494:pharmacology / Q000627:therapeutic use; D000090:Acetoacetates / Q000494:pharmacology / Q000627:therapeutic use; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000517:prevention & control / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D003071:Cognition / Q000187:drug effects*; D003864:Depression, Chemical; D004195:Disease Models, Animal; D007657:Ketone Bodies / Q000494:pharmacology* / Q000627:therapeutic use*; D007858:Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008822:Mice, Transgenic; D009245:NADH Dehydrogenase / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism*; D013268:Stimulation, Chemical
chemical_list: D000090:Acetoacetates; D016229:Amyloid beta-Peptides; D007657:Ketone Bodies; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C016635:acetoacetic acid; D009245:NADH Dehydrogenase; D020155:3-Hydroxybutyric Acid
keywords: Acetoacetate; Alzheimer's disease; Ketones; Mitochondria; β-hydroxybutyrate