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Ketogenic Diet Blunts the Fall of Long-Term Potentiation in an Alzheimer’s mouse model and Stimulates Synaptic Plasticity Pathway Enzymes

ABSTRACT: The Ketogenic Diet (KD) has been shown by two groups to improve cognition, memory and longevity in aged C57BL6 mice. We tested the impact of 7 months feeding the isocaloric Ketogenic Diet (KD) vs. the isocaloric standard carbohydrate-rich control diet (CD) in a mouse model of Alzheimer’s disease, APP/PS1. The KD vs. CD diets produced no significant changes in fat mass, lean Mass, or total body mass, or A-beta levels in brain. While the CD-fed APP/PS1 mice demonstrated the expected loss of Long-Term-Potentiation (LTP), LTP was completely preserved in KD-fed APP/PS1 mice to wild-type levels. RNAseq was carried out from these CD and KD-fed mouse brains, in the resulting Ingenuity Pathway Analysis the top 6 pathways induced in APP/PS1 brains on KD related to Synaptic Plasticity. Multiple biochemical elements of this pathway were evaluated in CD and KD hippocampi. Significant elevations of phospho-Erk and phospho-CREB were observed in KD vs. CD, and significant elevations of BDNF were observed in KD vs. CD females. The major effector of KD’s benefit is considered to be beta-hydroxybutyrate (BHB). BHB levels were significantly elevated in KD vs. CD mice, and fasting BHB levels were higher in females than male. We suggest that KD may rescue LTP not by reducing A-beta amyloid levels, but through higher BHB that may support greater synaptic plasticity in the face of A-beta amyloid synaptic challenge.

ORGANISM(S): Mus musculus

PROVIDER: GSE230469 | GEO | 2023/12/31

REPOSITORIES: GEO

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Project description:Beta-hydroxybutyrate (BHB) is a ketone body synthesized during fasting or strenuous exercise. Our previous study demonstrated that a cyclic ketogenic diet (KD), which induces BHB levels similar to fasting every other week, reduces midlife mortality and improves memory in aging mice. BHB actively regulates gene expression and inflammatory activation through non-energetic signaling pathways. Neither of these activities has been well-characterized in the brain and they may represent mechanisms by which BHB affects brain function during aging. First, we analyzed hepatic gene expression in an aging KD-treated mouse cohort using bulk RNA-seq. In addition to the downregulation of TOR pathway activity, cyclic KD reduces inflammatory gene expression in the liver. We observed via flow cytometry that KD also modulates age-related systemic T cell functions. Next, we investigated whether BHB affects brain cells transcriptionallyin vitro. Gene expression analysis in primary human brain cells (microglia, astrocytes, neurons) using RNA-seq shows that BHB causes a mild level of inflammation in all three cell types. However, BHB inhibits the more pronounced LPS-induced inflammatory gene activation in microglia. Furthermore, we confirmed that BHB similarly reduces LPS-induced inflammation in primary mouse microglia and bone marrow-derived macrophages (BMDMs). BHB is recognized as an inhibitor of histone deacetylase (HDAC), an inhibitor of NLRP3 inflammasome, and an agonist of the GPCR Hcar2. Nevertheless, in microglia, BHB's anti-inflammatory effects are independent of these known mechanisms. Finally, we examined the brain gene expression of 12-month-old male mice fed with one-week and one-year cyclic KD. While a one-week KD increases inflammatory signaling, a one-year cyclic KD reduces neuroinflammation induced by aging. In summary, our findings demonstrate that BHB mitigates the microglial response to inflammatory stimuli, like LPS, possibly leading to decreased chronic inflammation in the brain after long-term KD treatment in aging mice.

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Ketogenic Diet Blunts the Fall of Long-Term Potentiation in an Alzheimer’s mouse model and Stimulates Synaptic Plasticity Pathway Enzymes

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