Ketogenic diet or BHB improves epileptiform spikes, memory, survival in Alzheimer’s model

Abstract

The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/136226 doi: bioRxiv preprint first posted online May. 9, 2017; 3 hAPPJ20 (APP) mice carry a human APP transgene with the Swedish and Indiana 1 familial AD-causing mutations (J20 line) 10 and display amyloid deposition, cognitive 2 deficits, spontaneous epileptiform spikes, and high early mortality 5,11 . In order to test if a 3 ketogenic diet would suppress epileptiform spikes in hAPPJ20 mice, we designed a pair 4 of diets matched for protein content and micronutrients: normal high-carbohydrate 5 control diet based on AIN-93M (Control), and a zero-carbohydrate ketogenic diet (KD) 6 (Fig. 1a). In pilot experiments, we found that initiation of KD did not change caloric 7 intake (Fig. 1b), but resulted in a sustained increase of blood β-hydroxybutyrate (BHB) 8 levels similar to that of an overnight fast (Fig. 1c). We then followed a cohort of 9 hAPPJ20 mice undergoing serial 23-hour EEG recordings (EEGs) under three 10 conditions: on control diet, on the second day after starting KD, and during one day of 11 fasting ( Fig. 1d). Mice recovered on the control diet for 3 weeks between the KD and 12 fasting recordings. 13 14We observed that KD, but not fasting, suppressed the rate of epileptiform spikes by 15 approximately 40% (Fig 1e and 1f). Spike suppression was consistently observed 16 throughout the 23-hour recordings on KD (Figs. 1g). Spike suppression was also 17 consistent between individual mice on KD, while fasting exacerbated spikes in some 18 mice (Fig. 1h). To further explore the kinetics of EP spike suppression, we obtained 19EEGs with a separate cohort of mice that alternated from control diet to KD and back to 20 control over a period of 3 weeks (Fig. 1i). Spikes were suppressed while on KD, but 21 rebounded to prior frequency immediately after returning to the control diet (Figs. 1j and 22 1k). We then followed two parallel cohorts of hAPPJ20 mice fed control diet of KD for 23 peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/136226 doi: bioRxiv preprint first posted online May. 9, 2017; 4 three months, with nine EEG sessions during the latter half of this period (Fig. 1l). This 1 chronic feeding of KD suppressed EP spikes similarly to the earlier acute feedings (Figs 2 1m and 1n). 3 4 KD is a complex, pleiomorphic intervention with many potential mechanisms for 5 epileptiform spike suppression, including both energetic and signaling functions of BHB, 6 reduced insulin levels, provision of substrates for fatty acid oxidation, and many others 12 . 7To test if BHB is the active component of KD in spike suppression, we developed a set 8 of novel small molecules consisting of six-or eight-carbon fatty acids ester-linked to 9 BHB (Fig. 2a). Compound C6-BHB increased plasma BHB levels the most after 10 intraperitoneal injection of equimolar amounts into mice fed a control diet (Fig. 2b) 11 with...

Ketogenic Diets Alter the Gut Microbiome Resulting in Decreased Intestinal Th17 Cells

“…The synthesis method for the hexanoyl hexyl b-hydroxybutyrate (C6x2-bHB) ester was developed by Scott Ulrich of Ithaca College (Ithaca, New York, USA) as previously described (Newman et al, 2017b), and the ester was then custom ordered in bulk from AK Scientific (Union City, CA). The bHB moiety of the ester is chiral, and the compound was synthesized as an enantiomeric mixture.…”

Ketone ester-what’s in a name? Ambiguity begets uncertainty

“…Categories 1 through 6 shown below, along with Figures 1 – 4 , are “ketone esters”, or compounds used to synthesize ketone esters, which are independently capable of elevating circulating ketone bodies-those compounds being 1,3-butanediol and mid-chain carboxylic acids and alcohols. Six ketone esters cover the bulk of studies performed to date, those coming from the Brunengraber group, category 3A.ii ( Desrouchers et al, 1995 ), the Veech/Clarke groups, category 3A.i ( Clarke et al, 2012 ), the Hashim group, category 4A.i ( Hashim, 2014 ) and the Buck Institute, categories 2C.iii.2 and 3B.iii ( Newman et al, 2017 ), ( Stubbs et al, 2021 ) along with medium chain triglycerides, category 4A.ii. Immediately obvious from the structures shown in Figures 1 – 4 are the additional number of compounds possible.…”

β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain

“…A non-obesogenic ketogenic diet extends lifespan in mouse models and improves healthspan outcomes, including memory, in aged mice [28][29][30] . Additionally, ketogenic diet and exogenous ketones have been shown to improve cognitive and motor behavior in several mouse models of AD [31][32][33][34] . Early human studies of ketogenic compounds have improved cognitive scores in patients with mild to moderate AD [35][36][37][38][39][40] .…”

“…This work identifies bHB as a global regulator of cytosolic protein solubility, and identifies new metabolism-related mechanistic targets for therapeutic development in aging and AD. RESULTS b-hydroxybutyrate directly induces protein insolubility without posttranslational modification We, and other laboratories, have shown that memory phenotypes in aged mice and mouse models of Alzheimer disease (AD) can be improved with ketogenic therapies [28][29][30][31][32] . While the substrate provision for brain energy metabolism is likely indirectly assisting with these improvements, no direct mechanism has been validated.…”