Ketones block amyloid entry
and improve cognition in an
Yin JX1, Maalouf M1, Han P1, Zhao M2, Gao M3, Dharshaun T3, Ryan C4,
Whitelegge J4, Wu J3, Eisenberg D2, Reiman EM5, Schweizer FE6, Shi J7.
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.
Copyright © 2016 Elsevier Inc. All rights reserved.
Acetoacetate; Alzheimer's disease; Ketones; Mitochondria; β-hydroxybutyrate