Ketogenic diet and BHB rescue the fall of long-term potentiation in an Alzheimer's mouse model and stimulates synaptic plasticity pathway enzymes.
Level 5 - mechanism / opinion, no new human data
Preclinical animal model (transgenic mice) and ex vivo tissue assays.
PubMed 38366025 · doi:10.1038/s42003-024-05860-z
What was done
APP/PS1 transgenic Alzheimer's disease mouse models were fed either a ketogenic diet (KD) or a control diet (CD) for 7 months. Researchers evaluated hippocampal long-term potentiation (LTP), amyloid-beta (Aβ) levels, circulating beta-hydroxybutyrate (BHB) levels, and the direct effect of BHB on hippocampal LTP. Brain tissue was analyzed via RNA sequencing and targeted assays for synaptic plasticity enzymes (p-ERK, p-CREB) and brain-derived neurotrophic factor (BDNF).
What was found
KD significantly restored LTP to wild-type levels in APP/PS1 mice without altering Aβ levels. Blood BHB levels rose significantly in KD mice, and BHB application directly rescued LTP in APP/PS1 hippocampi. Brain RNA sequencing showed the top 6 upregulated pathways were related to synaptic plasticity. KD significantly increased p-ERK and p-CREB in both sexes and increased BDNF in female APP/PS1 mice. The abstract reported no specific numerical values or confidence intervals.
Why it matters
This study demonstrates a potential amyloid-independent mechanism by which ketogenic diets and BHB rescue synaptic plasticity deficits in an Alzheimer's disease model. It offers mechanistic preclinical support for exploring BHB and ketogenic interventions in early human cognitive decline.
Limits
The study is restricted to a rodent model (APP/PS1 mice) and ex vivo hippocampal slices, which may not replicate human Alzheimer's pathology or clinical progression. The abstract does not report the animal sample size, exact quantitative measurements, or behavioral cognitive outcomes.
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