Fasting effect on mitochondria bio-genesis in E4s? - ApoE4 Forum

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Fasting effect on mitochondria bio-genesis in E4s?

by Janelle » Sun Jan 26, 2014 5:07 pm

I came across this discussion, and it made me
wonder about the potential benefits of short-term fasting for E4s? I
can't find backing research, but you guys seem to be better at this kind
of thing, so I thought I would ask. Have you guys heard about any
research on this front?

http://blog.trackyourplaque.com/2011/08 ... t-all.html

ApoE4
degrades easiest of all ApoE forms, leaving protein fragments in cell’s
cytosol which then can affect a mitochondria’s lipid binding region
impairing the performing of tasks. In addition ApoE4 fragments diminish
gene PPAR gamma expression; and this depresses the desirable bio-genesis
of mitochondria. The affects on mitochondria may be why high levels of
dietary fat is problematic for ApoE4 individuals; there may be too
sparse output of viable mitochondria and mitochondria membranes are
involved in how efficiently we burn fat or glucose.

In light of
these ApoE4 nuances it is interesting to know that fasting raises free
fatty acid levels (from fats in the body and not loose fats from recent
food); and then those free fatty acids upregulate gene for PPAR gamma in
the liver. Fasting makes one put out ketones because of the extra PPAR
gamma programing and this ketogenesis is also one way that activating
more PPAR gamma improves insulin sensitivity. This suggests to me that
individuals with ApoE4 may (?) find some benefit from modified fasting;
possibly something like decidedly fewer meals in a day and also simply
not grazing on snacks (ie: in addition to just trying to select what
foods to eat) between meals that are regularly spaced apart (ie: very
early breakfast to let meal times spread put more evenly)

Would
one of you guys mind translating this too? It sounds like he's
suggesting that fasting would help burn up the protein fragments in our
cytoplasm?

Janelle

Contributor

 

Posts: 14

Joined: Fri Jan 24, 2014 2:49 pm

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Re: Fasting effect on mitochondria bio-genesis in E4s?

by Juliegee » Sun Jan 26, 2014 5:19 pm

LOL, Janelle, I won't even try to translate that passage. I'll leave THAT for the scientists among us
But, I did want to share that my neurologist strongly advises in favor
of both caloric restriction and fasting as an Alzheimer's prevention
tool. He also advises a low carb diet in order to generate ketones for
fuel. This is a controversial dietary strategy for E4's as benefits have
yet to be proven.

I maintain a low BMI, typically eat twice a
day, and often let 16+ hours go between meals. Many of us practice
caloric restriction (CR) and intermittent fasting (IF.)

Juliegee

Mod

 

Posts: 468

Joined: Sat Oct 26, 2013 5:36 pm

Peroxisome proliferator-activated receptor gamma - Wikipedia, the free encyclopedia



PPAR-gamma has been implicated in the pathology of numerous diseases
including obesity, diabetes, atherosclerosis, and cancer. PPAR-gamma agonists have been used in the treatment of hyperlipidaemia and hyperglycemia.^[18] PPAR-gamma decreases the inflammatory response of many cardiovascular cells, particularly endothelial cells.^[19] PPAR-gamma activates the PON1 gene, increasing synthesis and release of paraoxonase 1 from the liver, reducing atherosclerosis.<sup>[20]



PPARG regulates fatty acid storage and glucose metabolism. The genes activated by PPARG stimulate lipid uptake and adipogenesis by fat cells. PPARG knockout mice fail to generate adipose tissue when fed a high-fat diet.[6]</sup>

Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):6207-12. Epub 2005 Apr 15.

Deletion of PPARgamma in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance.

Jones JR, Barrick C, Kim KA, Lindner J, Blondeau B, Fujimoto Y, Shiota M, Kesterson RA, Kahn BB, Magnuson MA.

Author information

Abstract

Peroxisome
proliferator-activated receptor gamma (PPARgamma) plays a crucial role
in adipocyte differentiation, glucose metabolism, and other
physiological processes. To further explore the role of PPARgamma in
adipose tissues, we used a Cre/loxP strategy to generate
adipose-specific PPARgamma knockout mice. These animals exhibited marked
abnormalities in the formation and function of both brown and white
adipose tissues. When fed a high-fat diet, adipose-specific PPARgamma
knockout mice displayed diminished weight gain despite hyperphagia, had
diminished serum concentrations of both leptin and adiponectin, and did
not develop glucose intolerance or insulin resistance. Characterization
of in vivo glucose dynamics pointed to improved hepatic glucose
metabolism as the basis for preventing high-fat diet-induced insulin
resistance. Our findings further illustrate the essential role for
PPARgamma in the development of adipose tissues and suggest that a
compensatory induction of hepatic PPARgamma may stimulate an increase in
glucose disposal by the liver.

PMID:

15833818

[PubMed - indexed for MEDLINE]

PMCID:

PMC556131

Free PMC Article

Images from this publication.See all images (6)Free text

 



 

Best type of exercise for ε4s - ApoE4 Forum • View topic

ApoE4 Forum • View topic - Best type of exercise for ε4s

ApoE4 Forum • View topic - Best type of exercise for ε4s

Re: Best type of exercise for ε4s

 I worry that the research showing (for ex.) increased BDNF with very intense exercise does apply to us, which means it might even be more important for us, than others, to engage in intense exercise.

by Juliegee » Mon Dec 16, 2013 11:12 am

Here's a good common sense look at exercise.
Cordain (et.al.) surmises that much of today's chronic illness is the
result of an indoor sedentary life, Might help explain WHY E4s in
developing countries don't go on to develop AD or CVD.(Unfortunately,
E4s are not specifically addressed.)



Organic Fitness: Physical activity consistent with our Hunter-Gatherer Heritage

http://thepaleodiet.com/wp-content/uplo ... s_Med1.pdf

ApoE4 Forum • View topic - Best type of exercise for ε4s

ApoE4 Forum • View topic - Best type of exercise for ε4s

Re: Best type of exercise for ε4s

 I worry that the research showing (for ex.) increased BDNF with very intense exercise does apply to us, which means it might even be more important for us, than others, to engage in intense exercise.

by Juliegee » Mon Dec 16, 2013 11:12 am

Here's a good common sense look at exercise.
Cordain (et.al.) surmises that much of today's chronic illness is the
result of an indoor sedentary life, Might help explain WHY E4s in
developing countries don't go on to develop AD or CVD.(Unfortunately,
E4s are not specifically addressed.)



Organic Fitness: Physical activity consistent with our Hunter-Gatherer Heritage

http://thepaleodiet.com/wp-content/uplo ... s_Med1.pdf

ApoE4 - Wiki (boutique)

ApoE4

Contents

• 1 About this wiki
• 2 Introduction
• 3 Encouraging ApoE4 research
• 4 Interesting Alzheimer's research projects
• 5 Possible modulators of ApoE4-associated pathology
  
  • 5.1 Coffee (and caffeine)
  • 5.2 Omega-3 (n-3) fatty acids
  • 5.3 Alcohol consumption
  • 5.4 Turmeric and curcumin
  • 5.5 Blood Sugar
  • 5.6 Coconuts and coconut products
  • 5.7 Inflammation and LPS (lipopolysaccharides)
• 6 Biomarkers
• 7 Resources -- Events
• 8 Resources -- learning more about APOE
• 9 Resources -- where to buy supplements, olive oil, etc.
• 10 Resources -- APOE-aware healthcare practitioners
• 11 Notes

About this wiki

This wiki was created in order to organize information about how to
prevent and treat ApoE4-associated pathology. (See Notes, below, for
rationale.) As of early 2014, the page is still very much under
construction, but much more information will be added in the coming
weeks and months -- especially if you, the reader, contribute! Visit the wiki development forum at apoe4.info
if you have questions about how to contribute or ideas about how these
pages should be organized. (Or click on the "Discussion" tab above for
thoughts specific to this introductory page.)

Introduction

The ε4 variant of the APOE gene is famous for conferring a significantly higher risk for Alzheimer's disease, but numerous other diseases have been linked to it, including, to name a few, other forms of dementia,
heart disease, and gallbladder stones. Much of the focus of this wiki
space will nonetheless likely be on Alzheimer's disease and other forms
of dementia, since dementia is what most ε4 carriers are concerned
about, given the devastating consequences of dementia and the current
lack of effective treatment for it.



While the focus of the wiki will be on illness and its prevention and treatment, it should be noted that possessing an APOE-ε4 allele
is not an entirely bad thing for health. A few minor health advantages
seem to be conferred by ApoE4, among them, greater absorption or
production via sunlight of vitamin D, resistance to malnutrition in
children with conditions causing frequent diarrhea [1], protection against severe liver disease caused by hepatitis C [2], and slightly greater intelligence in youth [3].

Buck Institute finds link between ApoE4 and anti-aging protein targeted by resveratrol in red wine

Buck Institute finds link between ApoE4 and anti-aging protein targeted by resveratrol in red wine

Published on October 22, 2013 at 2:51 AM · 
 

The major genetic risk factor for Alzheimer's disease (AD), present in about two-thirds of people who develop the disease, is ApoE4, the cholesterol-carrying protein that about a quarter of us are born with.
But one of the unsolved mysteries of AD is how ApoE4 causes the risk for the incurable, neurodegenerative disease. In research published this week in The Proceedings of the National Academy of Sciences, researchers at the Buck Institute found a link between ApoE4 and SirT1, an "anti-aging protein" that is targeted by resveratrol, present in red wine.

The Buck researchers found that ApoE4 causes a dramatic reduction in SirT1, which is one of seven human Sirtuins. Lead scientists Rammohan Rao, PhD, and Dale Bredesen, MD, founding CEO of the Buck Institute, say the reduction was found both in cultured neural cells and in brain samples from patients with ApoE4 and AD. "The biochemical mechanisms that link ApoE4 to Alzheimer's disease have been something of a black box. However, recent work from a number of labs, including our own, has begun to open the box," said Bredesen.

The Buck group also found that the abnormalities associated with ApoE4 and AD, such as the creation of phospho-tau and amyloid-beta, could be prevented by increasing SirT1. They have identified drug candidates that exert the same effect. "This research offers a new type of screen for Alzheimer's prevention and treatment," said Rammohan V. Rao, PhD, co-author of the study, and an Associate Research Professor at the Buck, "One of our goals is to identify a safe, non-toxic treatment that could be given to anyone who carries the ApoE4 gene to prevent the development of AD."

 

In particular, the researchers discovered that the reduction in SirT1 was associated with a change in the way the amyloid precursor protein (APP) is processed. Rao said that ApoE4 favored the formation of the amyloid-beta peptide that is associated with the sticky plaques that are one of the hallmarks of the disease. He said with ApoE3 (which confers no increased risk of AD), there was a higher ratio of the anti-Alzheimer's peptide, sAPP alpha, produced, in comparison to the pro-Alzheimer's amyloid-beta peptide. This finding fits very well with the reduction in SirT1, since overexpressing SirT1 has previously been shown to increase ADAM10, the protease that cleaves APP to produce sAPP alpha and prevent amyloid-beta.

AD affects over 5 million Americans - there are no treatments that are known to cure, or even halt the progression of symptoms that include loss of memory and language. Preventive treatments are particularly needed for the 2.5% of the population that carry two genes for ApoE4, which puts them at an approximate 10-fold higher risk of developing AD, as well as for the 25% of the population with a single copy of the gene. The group hopes that the current work will identify simple, safe therapeutics that can be given to ApoE4 carriers to prevent the development of Alzheimer's disease

A Genetic Approach to the ApoE4 Puzzle | ALZFORUM

A Genetic Approach to the ApoE4 Puzzle | ALZFORUM

For decades, scientists have wondered how ApoE4, the strongest genetic risk factor for Alzheimer’s disease, influences pathology. They know the allele affects cells and tissues in many ways, but which actually lead to AD? Researchers led by Asa Abeliovich at Columbia University, New York, outline a new approach to answer the question in the July 24 Nature online. They compared transcriptomes of healthy ApoE4 carriers to those of LOAD patients who do not carry this gene, and found common patterns of gene expression. Genes regulating endocytosis and the processing of the amyloid β precursor protein (APP) stood out, hinting that ApoE4 primes the brain for APP-related changes that lead to AD, suggested the authors. “The data jibe with longstanding human and mouse data showing that ApoE4 enhances brain amyloid pathology,” wrote Samuel Gandy, Mount Sinai Medical Center, New York to Alzforum in an email. “It is heartening to think that after 20 years of ApoE4 linkage to AD, there are new exciting leads that might offer an explanation.” However, he noted some caveats (see full comment below).

Studies of humans, mice, and cultured cells suggest that ApoE4 impairs Aβ degradation and clearance, and encourages inflammation and endocytosis, which create even more Aβ (see Castellano et al., 2011; Koistinaho et al., 2004; Zhu et al., 2012; and He et al., 2007). However, it is unclear if all or any of these effects cause AD, result from it, or even relate to the disease, said co-first author Herve Rhinn. He and colleagues wanted to figure out what changes occur first as a way of getting closer to the root causes of the disease.

To do that, Rhinn and co-first author Ryousuke Fujita looked for transcript alterations in the cerebral cortex of postmortem brains from 185 healthy people grouped by ApoE status. The analysis revealed more than 8,000 genes that were expressed differently in people who carried the ApoE4 allele compared to those with ApoE2 or E3. Of those hits, 215 turned up in a separate analysis comparing expression in 86 LOAD patients and 67 age-matched controls, all without ApoE4. These genes may be key to AD risk endowed by ApoE, suggested the authors.


Genetic overlap among aging, ApoE4, and LOAD.

Image courtesy Herve Rhinn and Nature

Curiously, the ApoE4 pattern barely overlapped with that seen when the researchers compared gene expression among 64 older (age 85 and up) and 56 younger brains (age 75 or less). This suggested to the authors that ApoE and aging—the major risk factor for late onset AD (LOAD)—contribute to the disease via separate mechanisms (see figure below). The implication is that “different genetic forms or subtypes of Alzheimer’s disease may have specific underlying mechanisms and respond differently to treatment,” wrote Vivek Swarup and Daniel Geschwind of the University of California, Los Angeles, in an accompanying editorial.

To find out what mediated the differences in expression, the researchers applied a systems biology approach called differential co-expression analysis (DCA), which weighs results based on co-regulated genes (see ARF related news story). This identified 20 "master regulators" of the 215 genes. Researchers had previously associated the top hit, the zinc-binding protein RNF219, with cognitive performance, lipid metabolism, and brain ventricular volume. Another candidate—the synaptic vesicle protein SV2A—helps regulate neuronal endocytosis. Scientists had previously tied several of the regulators, including APBA2, ITM2B, and FYN, to the processing and intracellular trafficking of APP. Fyn kinase has also been linked to Aβ toxicity via tau (see ARF related news story).

To test whether these 20 genes bring about ApoE4’s effects, Rhinn and colleagues used small hairpin RNAs to knock down several individually in mouse N2a neuroblastoma cells and gauge how the cells reacted to added human recombinant ApoE4. This treatment spurred production of Aβ40 and Aβ42 in wild-type N2a cells, but not when the genes were knocked down.

The researchers then took a closer look at RNF219 and SV2A. Knocking down either prevented ApoE4 from boosting β–secretase 1 (BACE1) processing of APP, which it does in wild-type cells by promoting co-localization of BACE1 and APP in endosomes. Levetiracetam, an SV2A inhibitor used to treat epileptic seizures, also reduced Aβ production in N2a cells as well as in neurons induced from human fibroblasts donated by ApoE4 carriers. Together, these results suggest that RNF219 and SV2A mediate ApoE4’s effects on APP processing, concluded the authors.

Previous studies suggested that levetiracetam lowers neuronal hyperactivity and improves cognition in J20 mice. Interestingly, other anti-epileptic drugs, which have no affinity for SV2A, failed to achieve the same result (see ARF related news story). “We think levetiracetam works by reducing Aβ,” Abeliovich told Alzforum. “Our work reframes existing data, and suggests that hitting this target [SV2A] could be disease-altering,” he said. Michela Gallagher, Johns Hopkins University, Baltimore, Maryland, who previously reported that levetiracetam improved memory in people with mild cognitive impairment (see ARF related news story), agreed. “This report has potential therapeutic implications in support of SV2A as a target to prevent LOAD, at least in ApoE4 carriers,” Gallagher wrote to Alzforum in an email (see full comment below). She pointed out that benefits of levetiracetam extend to mice and humans that do not carry ApoE4, so the drug could help a broader population.

Scott Small, also at Columbia University, pointed out that the data support a hypothesis, summarized in his review written with Gandy, that any defect that keeps APP and BACE1 in endosomes will increase Aβ production and drive pathology (see Small and Gandy, 2006).

Other experts cautioned that the paper was still speculative, and required more exploration. “It will be interesting to see if the function of SV2A and RNF219 described here in cell culture can be reproduced in AD animal models,” wrote Lars Ittner, University of New South Wales, Sydney, Australia, to Alzforum via email (see full comment below). Ittner pointed out that how these ApoE4-driven changes relate to tau remains to be seen. Gandy cautioned that in other cultured neural cells, ApoE4 does not modify APP sorting or processing (see Biere et al., 1995).

Abeliovich plans to test if and how the other hits from this DCA study influence disease progression. In addition, he will extend this analysis beyond ApoE4 to other risk variants identified in genome-wide association studies for AD, and apply the method to Parkinson’s disease (see ARF related news story).—Gwyneth Dickey Zakaib.

References:

Rhinn H, Fujita R, Qiang L, Cheng R, Lee JH, Abeliovich A. Integrative genomics identifies APOE ε4 effectors in Alzheimer’s disease. Nature. 2013 July 24. [Epub ahead of print] Abstract.
Swarup V, Geschwind DH. From big data to mechanism. Nature. 2013 July 24. [Epub ahead of print] Abstract

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Comments on this content

1. • Barry Greenberg University Health Network, Toronto
   • Posted: 31 Jul 2013
   I read this paper with keen interest yesterday, but also found myself uneasy with the recombinant ApoE cell treatments as noted by Sam Gandy. Following my reading of his comments today, I took another look at that paper with a different view, asking if these points diminished my initial enthusiasm. I arrived at the conclusion that even if all of the recombinant ApoE treatment studies were removed from the paper as potentially artifactual, the conclusions of the authors still stand on the basis of the differential co-expression analyses and the experiments with the human induced neuronal cultures.…More
   
   
   View all comments by Barry Greenberg

Comments on Primary Papers for this Article

1. • Arnold Bakker Johns Hopkins Universiy
   • Posted: 27 Jul 2013
   • Primary Paper: 
   •  
   Apart from aging itself, apolipoprotein E (Apo-E) polymorphic alleles are the primary genetic determinants of risk for sporadic late onset Alzheimer disease (LOAD). Rhinn et al. have uncovered a candidate effector pathway for Apo-E4 on amyloid beta precursor protein (APP) endocytosis and metabolism contributing to LOAD. In addition to advancing biological understanding, the report has potential therapeutic implications in support of Sv2a as a target to prevent LOAD, at least in ApoE4 carriers. Would the Sv2a inhibitor used to suppress altered APP processing in APOE4-positive human induced neurons (hiNs) have in vivo efficacy in that population? …More
   
   
   While that remains to be seen, it is important to note that targeting Sv2a has shown beneficial effects in aging, MCI patients, and AD models apart from ApoE4. This is true for our (Bakker et al., 2012) and a second prior study using levetiracetam cited by the authors (Sanchez et al., 2012). 
   
   
   The AD mouse model used by Sanchez et al. is devoid of ApoE4 but showed improved cellular, network, and behavioral outcomes specific for mice with hAPP overexpression after treatment with the Sv2a ligand levetiracetam (see also Spiegel et al., 2013 for further evidence of a therapeutic benefit in a rodent model, absent ApoE4). Hyperactivity leading to network dysfunction is a common feature of these preclinical models. As Rhinn and colleagues noted, our report using low dose levetiracetam in amnestic mild cognitive impairment (MCI) ascribed therapeutic benefit to effective reduction of hippocampal hyperactivity. We have since completed additional cohorts of MCI patients under the same protocol (totaling N=54). In the aggregate MCI study population, 43 percent of the genotyped subjects were APOE4 carriers. The signature of hyperactivity localized within the hippocampal formation was not restricted to APOE4 carriers but was evident in carriers and non-carriers alike. 
   
   
   The notion that this condition contributes to disease progression is supported by a close association between the magnitude of hippocampal hyperactivity in MCI with the severity of structural atrophy in key AD related areas of the brain (Putcha et al., 2011). It is also notable that hippocampal hyperactivity is seen pre-symptomatically in early-onset AD (Quiroz et al., 2010) as well as in asymptomatic APOE4 carriers and in aMCI, irrespective of E4 carrier status. Hence, drugs that target Sv2a could be beneficial therapeutically in the broader context of prodromal AD, while not being limited to the ApoE4 population.
   View all comments by Arnold Bakker