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other·neurology, nutrition, preclinical research, biomedical research·PMC10873348

Ketogenic diet and BHB rescue the fall of long-term potentiation in an Alzheimer’s mouse model and stimulates synaptic plasticity pathway enzymes

Communications Biology · 12 authors, 6 centres

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TL;DR

In an APP/PS1 Alzheimer's mouse model, a 7-month ketogenic diet and beta-hydroxybutyrate (BHB) supplementation rescued long-term potentiation (LTP) deficits to wild-type levels, an effect linked to enhanced synaptic plasticity enzyme activation.

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This preclinical study investigated the effects of a ketogenic diet (KD) for 7 months versus a control diet on APP/PS1 Alzheimer's disease mice. The central result was that KD significantly rescued hippocampal long-term potentiation (LTP) to levels seen in wild-type C57BL/6 mice, and this effect was mimicked by ex vivo incubation with BHB. RNAseq analysis revealed KD induced six significant pathways related to synaptic plasticity. Biochemically, KD increased phosphorylated ERK and CREB in both sexes and brain-derived neurotrophic factor (BDNF) specifically in females. KD also reduced microglial activation markers. The study found no significant effect of KD on amyloid-β levels or body composition. Implications suggest KD and BHB may be therapeutically relevant for the earliest MCI phase of Alzheimer's disease.

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other

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neurology

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ORIGINAL PAPER

PMC10873348

Ketogenic diet and BHB rescue the fall of long-term potentiation in an Alzheimer’s mouse model and stimulates synaptic plasticity pathway enzymes

Communications Biology

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ABSTRACT

The Ketogenic Diet (KD) improves memory and longevity in aged C57BL/6 mice. We tested 7 months KD vs. control diet (CD) in the mouse Alzheimer’s Disease (AD) model APP/PS1. KD significantly rescued Long-Term-Potentiation (LTP) to wild-type levels, not by changing Amyloid-β (Aβ) levels. KD’s ‘main actor’ is thought to be Beta-Hydroxy-butyrate (BHB) whose levels rose significantly in KD vs. CD mice, and BHB itself significantly rescued LTP in APP/PS1 hippocampi. KD’s 6 most significant pathways induced in brains by RNAseq all related to Synaptic Plasticity. KD induced significant increases in synaptic plasticity enzymes p-ERK and p-CREB in both sexes, and of brain-derived neurotrophic factor (BDNF) in APP/PS1 females. We suggest KD rescues LTP through BHB’s enhancement of synaptic plasticity. LTP falls in Mild-Cognitive Impairment (MCI) of human AD. KD and BHB, because they are an approved diet and supplement respectively, may be most therapeutically and translationally relevant to the MCI phase of Alzheimer’s Disease.

CITATION EXPORT

Jacopo Di Lucente, Giuseppe Persico, Zeyu Zhou et al.. Ketogenic diet and BHB rescue the fall of long-term potentiation in an Alzheimer’s mouse model and stimulates synaptic plasticity pathway enzymes. Communications Biology. (2024). https://doi.org/10.1038/s42003-024-05860-z

AUTHORS

12 · 6 CENTRES

Jacopo Di Lucente, Giuseppe Persico, Zeyu Zhou, Lee-Way Jin, Jon J. Ramsey, Jennifer M. Rutkowsky, Claire M. Montgomery, Alexey Tomilov, Kyoungmi Kim, Marco Giorgio, Izumi Maezawa, Gino A. Cortopassi

1https://ror.org/05t6gpm70grid.413079.80000 0000 9752 8549Department of Pathology and MIND Institute, University of California Davis Medical Center, Sacramento, CA 95817 USA
2https://ror.org/02vr0ne26grid.15667.330000 0004 1757 0843Department of Experimental Oncology, European Institute of Oncology, IRCCS, 21041 Milan, Italy
3https://ror.org/05rrcem69grid.27860.3b0000 0004 1936 9684Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616 USA
4https://ror.org/05t6gpm70grid.413079.80000 0000 9752 8549Alzheimer’s Disease Research Center, University of California Davis Medical Center, Sacramento, CA 95817 USA
5grid.27860.3b0000 0004 1936 9684Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, CA 95616 USA
6https://ror.org/00240q980grid.5608.b0000 0004 1757 3470Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy