Triheptanoin Supplementation to Ketogenic Diet Curbs Cognitive Impairment in APP/PS1 Mice Used as a Model of Familial Alzheimer’s Disease
Ester Aso, Jana Semakova, Laura Joda, Vladislav Semak, Lyda Halbaut, Ana Calpena, Carmen Escolano, Jose C. Perales and Isidro Ferrer
Affiliation: Institut de Neuropatologia, Servei d’Anatomia Patologica, IDIBELL-Hospital Universitari de Bellvitge, C/Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Spain.
Diets containing a high proportion of fat with respect to protein plus carbohydrates are capable of inducing ketone
body production in the liver, which provides an energetic alternative to glucose. Some ketogenic diets have been
tested as therapeutic strategies for treating metabolic disorders related to a deficiency in glucose-driven ATP generation.
However, ketone bodies are not capable of providing extra tricarboxylic acid cycle intermediates, limiting the anabolic
capacity of the cell. Therefore, it is reasonable to hypothesize that supplementing a ketogenic diet with anaplerotic compounds
such as triheptanoin may improve ketogenic diet effectiveness. The present study tests this hypothesis in APP/PS1
(APPswe/PS1dE9) transgenic mice, used as a model of familial Alzheimer’s disease because impaired energy supply to
neurons has been linked to this neurodegenerative process. Triheptanoin supplementation to a ketogenic diet for three
months and starting at the age of three months reduces the memory impairment of APP/PS1 mice at the age of 6 months.
The Aβ production and deposition were not significantly altered by the ketogenic diet, supplemented or not by triheptanoin.
However, mice fed with triheptanoin-rich ketogenic diet have shown decreased astroglial response in the vicinity of
Aβ plaques and decreased expression of the pro-inflammatory cytokine interferon-γ in astrocytes. These findings correlate
with transcriptional up-regulation of the ROS detoxifying mechanisms Sirt1 and Pparg, thus linking triheptanoin with improved
mitochondrial status. Present findings support the concept that ketogenic diets supplemented with anaplerotic
compounds can be considered potential therapeutic strategies at early stages of Alzheimer’s disease.
Keywords: Alzheimer’s disease, anaplerotic diet, APP/PS1 transgenic mice, ketone bodies, mitochondria, triheptanoin
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