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APOΕ4 Lowers Energy Expenditure and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
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Re: APOΕ4 Lowers Energy Expenditure and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis

Postby PeterM » Sat Oct 24, 2020 3:36 pm

Naive question perhaps: Since impaired glucose uptake in the brain appears to detrimentally affect carriers of the Apoe4 allele, do we have any studies (or even good anecdotal evidence) demonstrating that being in constant (or near-constant) ketosis mitigates this glucose shortfall? I’m not hip to all the different kinds of PET scans etc that might precisely measure brain energy uptake, but it seems kind of extraordinary something so critical—and ostensibly simple to measure—hasn’t been better explored. Or maybe it has and I just can’t find it. Any input would be appreciated. Grazie.

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Re: APOΕ4 Lowers Energy Expenditure and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis

Postby TheresaB » Sun Oct 25, 2020 9:39 am

PeterM wrote:do we have any studies (or even good anecdotal evidence) demonstrating that being in constant (or near-constant) ketosis mitigates this glucose shortfall?


Yes, Dr Stephen Cunane has studied this and has written papers on it. Here's a presentation of his on the subject https://www.youtube.com/watch?v=pR8bHXZKZj8
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Re: APOΕ4 Lowers Energy Expenditure and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis

Postby PeterM » Sun Oct 25, 2020 3:49 pm

TheresaB wrote:
PeterM wrote:do we have any studies (or even good anecdotal evidence) demonstrating that being in constant (or near-constant) ketosis mitigates this glucose shortfall?


Yes, Dr Stephen Cunane has studied this and has written papers on it. Here's a presentation of his on the subject https://www.youtube.com/watch?v=pR8bHXZKZj8



Thanks, Theresa, somehow I missed this. In another more recent video of his that I just discovered he goes over some newer data not included in the aforementioned video. This info begins at 18:00. The whole video is under 28:00 so not a big commitment for those interested.
https://m.youtube.com/watch?v=XxGiQ7YrUYE

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Re: APOΕ4 Lowers Energy Expenditure and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis

Postby Tincup » Sun Oct 25, 2020 4:25 pm

PeterM wrote: In another more recent video of his that I just discovered he goes over some newer data not included in the aforementioned video. This info begins at 18:00. The whole video is under 28:00 so not a big commitment for those interested.
https://m.youtube.com/watch?v=XxGiQ7YrUYE


Nice find Peter! Too bad (for them) many folks won't exercise, do a keto diet or fast. The graphs pretty much lay out the energetic answer. If someone has enough money, ketone esters will do the trick for the unwilling. The late Richard Veech's goal was an inexpensive version of these esters (which he had a large hand in creating). He felt that widely available, inexpensive esters would solve many of these issues.
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Re: APOΕ4 Lowers Energy Expenditure and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis

Postby Fiver » Mon Oct 26, 2020 6:09 am

Hi everyone,I hope you're all well.

I have this paper on my reading list.

In case it's any help, I wrote a short summary of a previous but related article from the same research lab below.

The author was a speaker at an online seminar series in the spring and summer and presented this earlier work.


Alzheimer’s Afternoons Seminar: Lance Johnson
Alzheimer’s Disease: Tipping the energy balance
Alzheimer’s Afternoons Seminar Series
(March 26) Lance Johnson

The Alzheimer’s Afternoons Seminar Series started off with a seminar by Dr. Lance Johnson from the University of Kentucky. Dr. Johnson is one of the organizers of the popular online seminar series but also a guest editor (along with Allan Butterfield) for a special issue of the journal Neurobiology of Disease containing eleven articles on ApoE and Alzheimer’s. The open access articles (technically published in June 2020, but available online in April 2020) can be accessed here:

https://www.sciencedirect.com/journal/n ... 100&page=1

This seminar is based in part of a recent article in this series:

b2

Holden C. Williams, Brandon C. Farmer, Margaret A. Piron, Adeline E. Walsh, Ronald C. Bruntz, Matthew S. Gentry, Ramon C. Sun, Lance A. Johnson. APOE alters glucose flux through central carbon pathways in astrocytes. Neurobiology of Disease, Volume 136, 2020, 104742, ISSN 0969-9961. https://doi.org/10.1016/j.nbd.2020.1047 ... 6120300176)

Dr. Johnson opened by explaining the theory that carriers of the apoe4 risk gene, which significantly increases the incidence of late onset Alzheimer’s disease (LOAD), process metabolic “fuels” differently. Specifically, he cited increasing evidence that apoe4 astrocytes and microglia – brain cells which tend to neurons and fight infection – are less able to process sugars by the usual processes of glycoloysis, the citric acid cycle, and/or oxidative phosphorylation (OXPHOS). He postulated that this one reason why apoe4 astrocytes fail to adequately nurture and protect neurons.

He mentioned the Randle cycle (the “glucose fatty-acid cycle”) which helps cells fine-tune fuel usage. Normally, this cycle balances the competition of glucose and fatty acids for metabolic substrates in cells. (If you own a plug-in hybrid car think of this as the computer which constantly balances the use of the engine vs. the battery to drive the wheels.)

In recent years the inability to use glucose effectively has become a well-recognized hallmark of the disease.

Dr. Johnson hypothesized that apoe4 brain cells process glucose mainly through glycolysis, ending in the production of lactate.

Normally, this occurs when adequate oxygen for OXPHOS is lacking. It can also occur in cancerous tumors via the Warburg effect. In any case, converting glucose to lactate provides only a small amount of energy and requires that lactate – which becomes toxic when it accumulates – be recycled later, at significant metabolic cost. In short, it is a quick way to produce a bit of ATP and NAD, but quite inefficient.

His theory also predicts that apoe4 brains would use fats as an alternative fuel.

This may require some explanation for non-experts:

Fatty acids are simple chains of hydrocarbon molecules, with a small “head group”. They vary in length from short chain (e.g., having eight carbons; C-8) to long chain (e.g., having 18 carbons; C-18) and usually have an even number of carbons in the chain. Sometimes specific carbons are connected by double bounds, instead of single bonds; these “degrees of unsaturation” form kinks in the chain and change the molecule’s personality.

Double bond kinks can determine how fats “stack” or fit together. Fatty acids that stack well tend to be solid at room temperature and are called “fats”, whereas those with double bond kinks tend to require more personal space, are liquids at room temperature, and are commonly called “oils”.

Examples include: saturated fats (no double bonds), unsaturated fats (one double bond), poly-unsaturated fats (multiple double bonds), and trans- and partially hydrogenated- fats (mostly commercial food products; not healthy!), as well as omega-3 fatty acids (often anti-inflammatory) and omega-6 fatty acids (often pro-inflammatory).

For convenient storage fatty acids can be “hung” from a glycerol molecule – like belts on a clothes hanger. These are the monoglycerides (one hanging chain), diglycerides (two hanging chains), triglycerides (three hanging chains, good for storage and transport), or phospholipids (two hanging chains and a phosphate head group).

“Lipid” is a very general term. Lipids are, technically, anything similar that doesn’t dissolve easily in water – such as fatty acids, waxes, sterols, fat-soluble vitamins (A, D, E, and K), monoglycerides, diglycerides, triglycerides, and phospholipids.

By the way cholesterol is not a fat. It has a basic steroid structure, and is synthesized differently.

Brain tissues usually prefer to burn sugars as fuel. Burning fats as fuel first requires that larger triglycerides and longer chain fatty acids be trimmed to a size that can enter the mitochondria. Then is requires beta-oxidation of shorter-chain fatty acids inside mitochondrial matrix, a process that is slower and can produce more toxic reactive oxygen species (ROS) than the burning of sugars.

You’ll recall that fatty acids can be obtained from the diet and transported in the blood as triglycerides. Triglycerides are “oily” and not soluble in blood plasma; hence they are circulated (along with cholesterol) inside tiny lipoprotein particles. These particles include the familiar LDL (the “bad” cholesterol carrier) and HDL (the “good” cholesterol carrier), and many others. The liver is one of the main sources of cholesterol and lipids and acts as a distribution hub to build, export, and recycle apolipoprotein particles.

These particles contain some proteins – these serve as a scaffolding to help shape the particles into hollow spheres and also acts as an address label of sorts. Cells hoping to import cargo carried in lipoprotein particles display receptors to these proteins on their surfaces – and snag the particles as they pass by. ApoE (apolipoprotein E) is one of these proteins, present on the surface of many (but not all) types of lipoprotein particles. The apoe4 version of this protein differs only by one or two amino acids, but this give the molecule a different shape and different binding tendencies.

These familiar types of lipoprotein particles produced primarily by the liver – LDL, VLDL, IDL, and HDL – do not usually penetrate the blood-brain barrier. Thus, the brain is “cut-off” from dietary fats and lipids. Instead the brain produces its own fats, lipids, and cholesterol and shares them among the various types of brain cells in analogous lipoprotein particles that occur only in the brain. However, the apoe4 protein is a key component of lipoprotein particles found both inside and outside of the brain.

In some cases, brain cells that are particularly hungry for fats to burn as fuel can end up breaking down the protective myelin sheaths of neurons into free fatty acids. This would be problematic, of course.

Dr. Johnson noted the Dr. Alois Alzheimer observed “lipid droplets” in the brain of patients in 1907. Dr. Johnson’s research group wondered if these “droplets” were accumulations of fats and they wondered if individuals carrying apoe4 genes, and having a higher risk of developing LOAD, accumulated more lipid droplets in brain tissues. By analyzing brain tissues, they found interesting differences: apoe4 brain cells accumulation more droplets, but they are also smaller in diameter compared to apoe3 brain cells.

This might be explained in part by observation that apoe4 cells have lower activity of ATP-binding cassette transporters (ABC transporters) which facilitate lipid efflux from cells. ABC transporters load fats and lipids into lipoprotein particles for export; the presence of apoe4 reduces this, leaving apolipoproteins underinflated (or “poorly lipidated”, to use the technical term). This could explain the group’s observation. It would be expected that lipid droplets would accumulate inside apoe4 cells if lipids and fatty acids could not be exported as rapidly.

Dr. Johnson’s group noted that the accumulation of small lipid droplets in apoe4s worsen with age.

In another set of experiments, they fed apoe4 brain cells fatty acids labeled with radioactive carbon (14C) – a useful way to trace the path of these compounds in cells. They found that apoe4 cells were indeed burning more fatty acids by beta-oxidation in mitochondria, supporting their hypothesis.

To explore this further they conducted metabolic experiments on 94 human subjects (all <55 years old and healthy; 33 of these carried at least one copy of the apoe4 gene). The researchers recorded the subject’s metabolic activity – including their respiratory exchange ratio – at rest, then after consuming sugary drinks. They found that subjects without apoe4 genes (including those with the apoe2 genes, which is protective against LOAD) burned the sugars easily. They showed the typical increase in oxygen uptake that is expected when subjects are burning sugars as fuels. On the other hand, subjects with apoe4 genes did not metabolize sugars as well; they exhibited no increase in oxygen uptake or usage.

Their conclusion from this collection of experiments – some of which were recently published – was that the data support the original theory: apoe4 cells process sugars poorly and seem to use more fatty acids as fuel to compensate.

Dr. Johnson compared the metabolism of apoe4 astrocyctes and microglia to the “Warburg effect” seen in cancerous tumors. As mentioned previously many types of cancerous cells run glycolysis without the citric acid cycle and OXPHOS. This process is fast but inefficient. It churns out lactate acid as a waste product. He mentioned that a “high fat diet” made this more pronounced. NOTE: a “high-fat diet” usually refers to a poor-quality diet akin to a “Super-size Me”-type Standard American Diet, which is appropriately abbreviated as S.A.D.
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Re: APOΕ4 Lowers Energy Expenditure and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis

Postby floramaria » Tue Oct 27, 2020 6:27 pm

Fiver wrote:I wrote a short summary of a previous but related article from the same research lab below.
Thanks for the excellent summary. I appreciate your taking the time to write this up for us.
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Re: APOΕ4 Lowers Energy Expenditure and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis

Postby MarcR » Tue Oct 27, 2020 6:37 pm

I agree that Fiver's summary is excellent and would also like to thank everyone participating in this fantastic topic.

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Re: APOΕ4 Lowers Energy Expenditure and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis

Postby Tincup » Tue Oct 27, 2020 6:57 pm

Fiver wrote:I wrote a short summary of a previous but related article from the same research lab below.


I concur with Marc & Floramaria, great summary and thank you for posting it. Also I appreciate everyone's excellent contributions!
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Re: APOΕ4 Lowers Energy Expenditure and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis

Postby PeterM » Wed Oct 28, 2020 6:42 am

Yes, Fiver, that was a prodigious contribution. Sincerely appreciated.

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Re: APOΕ4 Lowers Energy Expenditure and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis

Postby Tincup » Fri Oct 30, 2020 8:58 pm

This is an excellent podcast on the topic and how ketones can modulate the effect. The meat of the podcast on this topic starts around 57:00. (StemTalk Episode 114: Lilianne Mujica-Parodi talks about how diet and ketones affect brain aging) Also this paper Diet modulates brain network stability, a biomarker for brain aging, in young adults

From the paper:
Significance
To better understand how diet influences brain aging, we focus here on the presymptomatic period during which prevention may be most effective. Large-scale life span neuroimaging datasets show functional communication between brain regions destabilizes with age, typically starting in the late 40s, and that destabilization correlates with poorer cognition and accelerates with insulin resistance. Targeted experiments show that this biomarker for brain aging is reliably modulated with consumption of different fuel sources: Glucose decreases, and ketones increase the stability of brain networks. This effect replicated across both changes to total diet as well as fuel-specific calorie-matched bolus, producing changes in overall brain activity that suggest that network “switching” may reflect the brain’s adaptive response to conserve energy under resource constraint.

Abstract
Epidemiological studies suggest that insulin resistance accelerates progression of age-based cognitive impairment, which neuroimaging has linked to brain glucose hypometabolism. As cellular inputs, ketones increase Gibbs free energy change for ATP by 27% compared to glucose. Here we test whether dietary changes are capable of modulating sustained functional communication between brain regions (network stability) by changing their predominant dietary fuel from glucose to ketones. We first established network stability as a biomarker for brain aging using two large-scale (n = 292, ages 20 to 85 y; n = 636, ages 18 to 88 y) 3 T functional MRI (fMRI) datasets. To determine whether diet can influence brain network stability, we additionally scanned 42 adults, age < 50 y, using ultrahigh-field (7 T) ultrafast (802 ms) fMRI optimized for single-participant-level detection sensitivity. One cohort was scanned under standard diet, overnight fasting, and ketogenic diet conditions. To isolate the impact of fuel type, an independent overnight fasted cohort was scanned before and after administration of a calorie-matched glucose and exogenous ketone ester (D-β-hydroxybutyrate) bolus. Across the life span, brain network destabilization correlated with decreased brain activity and cognitive acuity. Effects emerged at 47 y, with the most rapid degeneration occurring at 60 y. Networks were destabilized by glucose and stabilized by ketones, irrespective of whether ketosis was achieved with a ketogenic diet or exogenous ketone ester. Together, our results suggest that brain network destabilization may reflect early signs of hypometabolism, associated with dementia. Dietary interventions resulting in ketone utilization increase available energy and thus may show potential in protecting the aging brain.

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