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-hydroxybut...

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Veröffentlicht in:Neurobiology of aging 2016-03, Vol.39, p.25-37
Hauptverfasser: Yin, Jun Xiang, Maalouf, Marwan, Han, Pengcheng, Zhao, Minglei, Gao, Ming, Dharshaun, Turner, Ryan, Christopher, Whitelegge, Julian, Wu, Jie, Eisenberg, David, Reiman, Eric M, Schweizer, Felix E, Shi, Jiong
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Sprache:eng
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Zusammenfassung: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.
ISSN:0197-4580
1558-1497
DOI:10.1016/j.neurobiolaging.2015.11.018