Communications Biology · 12 authors, 6 centres
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A 7-month ketogenic diet (KD) rescued long-term potentiation (LTP) deficits in APP/PS1 Alzheimer’s mice to wild-type levels without reducing amyloid-β. The ketone body β-hydroxybutyrate (BHB) alone also rescued LTP, and KD activated synaptic plasticity enzymes p-ERK and p-CREB in both sexes. These findings suggest KD and BHB may be translationally relevant for the mild cognitive impairment phase of Alzheimer’s disease.
**Background:** Alzheimer’s disease (AD) is characterized by synaptic dysfunction and cognitive decline, with long-term potentiation (LTP) deficits appearing early. The ketogenic diet (KD) improves memory and longevity in aged wild-type mice, but its effects on synaptic plasticity in AD models were unclear. This study tested whether KD and its active metabolite β-hydroxybutyrate (BHB) could rescue LTP deficits in APP/PS1 mice and explored underlying mechanisms.
**Methods:** APP/PS1 mice (both sexes) were fed a KD (<0.5% carbohydrate, 90% fat) or control diet (CD, 74% carbohydrate) from 6 to 13 months of age. Hippocampal LTP was measured in CA3-CA1 slices after high-frequency stimulation. Blood BHB was measured in fed and fasted states. RNAseq was performed on cortex, and gene ontology analysis (Ingenuity Pathway Analysis) identified enriched pathways. Western blotting quantified phosphorylated ERK, CREB, CaMKII, and BDNF. Microglial markers (Iba1, CD11b, CD68, Dectin-1) and astrocyte marker GFAP were assessed. Aβ levels were measured by ELISA. Behavioral tests included open field, Y-maze, and Barnes maze. Ex vivo BHB (3 mM, 1-hour incubation) was tested on slices from 15-month-old APP/PS1 mice.
**Key Results:** KD significantly rescued both early and late-phase LTP in APP/PS1 mice to wild-type levels (Fig. 1a,b). Blood BHB was significantly higher in KD vs. CD mice in fed state (F(1,56)=70.96, p<0.001) and fasted state (F(1,56)=10.14, p=0.0024). BHB alone (3 mM, 1-hour) also rescued LTP in APP/PS1 slices (Fig. 1e,f). RNAseq identified 354 differentially expressed genes (p≤0.01); all 6 significant canonical pathways related to synaptic plasticity (e.g., CREB signaling, LTP, calcium signaling). KD significantly increased phospho-ERK (F(1,20)=19.97, p<0.001) and phospho-CREB (F(1,20)=10.84, p=0.004) in both sexes, but not CaMKII or PSD95. BDNF dimer was significantly increased only in KD-fed females (F(1,20)=9.156, p=0.007). KD did not alter Aβ levels. Microglial markers Iba1 (F(1,20)=16.60, p<0.001) and CD11b (F(1,20)=11.64, p=0.003) were significantly reduced; CD68 and Dectin-1 were reduced in males only. Astrocyte marker GFAP was unchanged. Behavioral tests showed increased exploration in KD-fed mice (open field p<0.05; Y-maze p<0.01) and a trend for improved working memory (Y-maze alternation p=0.061), but no significant effect on spatial memory in Barnes maze.
**Clinical Implications:** LTP decline is the earliest neurophysiological biomarker in both APP/PS1 mice and human AD, with a similar magnitude of fall (~36-37%) in the mild cognitive impairment (MCI) phase. KD and BHB, already approved for human use (epilepsy) and available as supplements, may be most translationally relevant for the MCI phase of AD. The study suggests KD/BHB rescue LTP through enhanced synaptic plasticity (p-ERK/p-CREB/BDNF pathway) and reduced microglial inflammation, without affecting Aβ burden. Rapid translation to human clinical trials for delaying MCI progression is proposed.