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Blocking PUFA Metabolism May Reverse Alzheimer Disease (AD)

haidut

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I posted a few studied showing PUFA and its metabolites are strongly involved in AD and brain aging in general.
Increased Pufa Oxidation May Be Biomarker For Alzheimers
Blocking Inflammation From PUFA Reverses Brain Aging

The second link above discussed specifically the inhibition of the lipoxygenase (LOX) enzyme, which synthesizes leukotrienes and other inflammatory mediators from PUFA. The study above used a leukotriene antagonist, which opposes the effects of the leukotrienes. An arguably better approach would be to inhibit the synthesis of those leukotrienes altogether, which is what this new study did. The enzyme inhibited by the study was ALOX15.
ALOX15 - Wikipedia

The drug used in this new study below was PD146176 and inhibiting the same pathway has been shown to be beneficial for a wide variety of pathologies like CVD, cancer, osteoporosis, BPH, etc. In light of this evidence, I am not sure what other evidence does the medical profession need to accept PUFA is bad.

http://www.biologicalpsychiatryjournal.com/article/S0006-3223(16)32428-3/abstract
https://www.sciencedaily.com/releases/2017/01/170105100948.htm
"...Inhibition of 12/15-lipoxygenase activated autophagy, the body's natural kill system for cells. The activation was associated with decreased levels of tau, suggesting that the inhibitor works by re-activating the neuronal autophagy machinery to clear cellular buildup of tau. The results indicate that pharmacological inhibition of 12/15-lipoxygenase reverses learning and memory impairments and reduces Aβ and tau neuropathology, even after their onset in aged mice. "Our findings have important translational value since they establish this protein enzyme as a novel and viable therapeutic target with real disease-modifying potential for AD," Praticò said."
 

WestCoaster

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This is why i'm always iffy when people post studies of any sort because you can always fun other studies to contradict each other. I used those links specifically because some are from Science Daily which is being referenced specifically in this article via your first link, and NCBI which many people around this forum like to reference. Some studies are using mice much like yours do.

The broad spectrum response: Ketogenic has positive effects on not only alzheimer's but dementia, schizophrenia, seizures, epilepsy, and others.

Starting off, lets look at a single link from NCBI covering a wide variety of neurological disorders and more using a ketogenic diet
Epilepsy, Aging, Parkinsons Disease, ALS, Alzeimers, Cancer, Strokes, Mitochondrial disorders, Brain Injuries, Depression, Autism, and Migraine headaches
The Ketogenic Diet as a Treatment Paradigm for Diverse Neurological Disorders


Then stand alone neurological disorders

Alzheimer's
Neuroprotective and disease-modifying effects of the ketogenic diet
https://www.sciencedaily.com/releases/2005/10/051017072307.htm

Dementia
Ketogenic Diet Shows Promising Results for All Dementia Stages (studies at the bottom)

Schizophrenia
https://www.sciencedaily.com/releases/2015/12/151217111711.htm

Epilepsy
The Ketogenic Diet: Uses in Epilepsy and Other Neurologic Illnesses
Ketogenic diet for treatment of epilepsy

Seizures
https://www.sciencedaily.com/releases/2005/11/051114220938.htm

What relation does ketogenic diet have with PUFA? Well going keto will definitely raise the PUFA consumption, but keto in itself doesn't recommend foods filled with PUFA. But when you consume animal meats, eggs, fish, cheese, eggs and the like, PUFA by default will go up quite a bit. Yet despite this, we have a slew of studies above that shows a keto diet in itself helps, protects, and/or reverses all of the above.
 

haidut

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This is why i'm always iffy when people post studies of any sort because you can always fun other studies to contradict each other. I used those links specifically because some are from Science Daily which is being referenced specifically in this article via your first link, and NCBI which many people around this forum like to reference. Some studies are using mice much like yours do.

The broad spectrum response: Ketogenic has positive effects on not only alzheimer's but dementia, schizophrenia, seizures, epilepsy, and others.

Starting off, lets look at a single link from NCBI covering a wide variety of neurological disorders and more using a ketogenic diet
Epilepsy, Aging, Parkinsons Disease, ALS, Alzeimers, Cancer, Strokes, Mitochondrial disorders, Brain Injuries, Depression, Autism, and Migraine headaches
The Ketogenic Diet as a Treatment Paradigm for Diverse Neurological Disorders


Then stand alone neurological disorders

Alzheimer's
Neuroprotective and disease-modifying effects of the ketogenic diet
https://www.sciencedaily.com/releases/2005/10/051017072307.htm

Dementia
Ketogenic Diet Shows Promising Results for All Dementia Stages (studies at the bottom)

Schizophrenia
https://www.sciencedaily.com/releases/2015/12/151217111711.htm

Epilepsy
The Ketogenic Diet: Uses in Epilepsy and Other Neurologic Illnesses
Ketogenic diet for treatment of epilepsy

Seizures
https://www.sciencedaily.com/releases/2005/11/051114220938.htm

What relation does ketogenic diet have with PUFA? Well going keto will definitely raise the PUFA consumption, but keto in itself doesn't recommend foods filled with PUFA. But when you consume animal meats, eggs, fish, cheese, eggs and the like, PUFA by default will go up quite a bit. Yet despite this, we have a slew of studies above that shows a keto diet in itself helps, protects, and/or reverses all of the above.

Where in my post did you see advocating against ketogenic diet or against eating high fat in general? The study is about a specific pathway using arachidonic acid (a type of PUFA) as a substrate and producing inflammatory mediators. Inhibiting either the activity of those mediators or the activity of the pathway (LOX) was found to be beneficial. Nothing in the study or my post said anything about ketogenesis.
If you really want to rebuff the study then please show me evidence that enhancing ALOX15 or administering leukotriene agonist (not sure this drug even exists) was protective against AD. Just showing ketogenic diet was good is not disproving the study as many saturated fats are themselves inhibitors of LOX and in general if you eat higher saturated fat as proportion it will protect from many of the negative PUFA effects.
Or am I missing something?
 

bradley

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Messages
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Dr. Fred Kummerow whom we interviewed for On the Back of a Tiger was doing a study on precisely this. They were working with an isotope that blocked oxidation of PUFA in the brain to see if it had effects on AD and other ND diseases.
 

haidut

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Dr. Fred Kummerow whom we interviewed for On the Back of a Tiger was doing a study on precisely this. They were working with an isotope that blocked oxidation of PUFA in the brain to see if it had effects on AD and other ND diseases.

Nice! So, I gather his view on PUFA is not very favorable then?
 

haidut

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Do you know how effective boswellic acids are at inhibiting 5-LOX? Specifically 3-O-acetyl-11-keto-ß-boswellic acid?

Life Extension makes a product that claims to do just that, but i haven't researched it myself.

5-LOX Inhibitor with AprèsFlex®, 100 mg, 60 vegetarian capsules

Thanks for the pointer, haven't look into that yet. Vitamin E, minocycline, ketotifen and possibly cyproheptadine are the LOX inhibitors I had looked at. It always helps to have a few extra options.
 

Koveras

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Joined
Dec 17, 2015
Messages
719
I posted a few studied showing PUFA and its metabolites are strongly involved in AD and brain aging in general.
Increased Pufa Oxidation May Be Biomarker For Alzheimers
Blocking Inflammation From PUFA Reverses Brain Aging

The second link above discussed specifically the inhibition of the lipoxygenase (LOX) enzyme, which synthesizes leukotrienes and other inflammatory mediators from PUFA. The study above used a leukotriene antagonist, which opposes the effects of the leukotrienes. An arguably better approach would be to inhibit the synthesis of those leukotrienes altogether, which is what this new study did. The enzyme inhibited by the study was ALOX15.
ALOX15 - Wikipedia

The drug used in this new study below was PD146176 and inhibiting the same pathway has been shown to be beneficial for a wide variety of pathologies like CVD, cancer, osteoporosis, BPH, etc. In light of this evidence, I am not sure what other evidence does the medical profession need to accept PUFA is bad.

http://www.biologicalpsychiatryjournal.com/article/S0006-3223(16)32428-3/abstract
https://www.sciencedaily.com/releases/2017/01/170105100948.htm
"...Inhibition of 12/15-lipoxygenase activated autophagy, the body's natural kill system for cells. The activation was associated with decreased levels of tau, suggesting that the inhibitor works by re-activating the neuronal autophagy machinery to clear cellular buildup of tau. The results indicate that pharmacological inhibition of 12/15-lipoxygenase reverses learning and memory impairments and reduces Aβ and tau neuropathology, even after their onset in aged mice. "Our findings have important translational value since they establish this protein enzyme as a novel and viable therapeutic target with real disease-modifying potential for AD," Praticò said."

Another one :)

Alzheimer's disease linked to the metabolism of unsaturated fats
https://www.sciencedaily.com/releases/2017/03/170322092355.htm

Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance: A nontargeted metabolomic study
 

High_Prob

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Mar 23, 2016
Messages
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Learning Impairments, Memory Deficits, and Neuropathology in Aged Tau Transgenic Mice Are Dependent on Leukotrienes Biosynthesis: Role of the cdk5 ... - PubMed - NCBI (6/7/2018)

Mol Neurobiol. 2018 Jun 7. doi: 10.1007/s12035-018-1124-7. [Epub ahead of print]
Learning Impairments, Memory Deficits, and Neuropathology in Aged Tau Transgenic Mice Are Dependent on Leukotrienes Biosynthesis: Role of the cdk5 Kinase Pathway.
Giannopoulos PF1, Chiu J1, Praticò D2.
Author information

Abstract
Previous studies showed that the leukotrienes pathway is increased in human tauopathy and that its manipulation may modulate the onset and development of the pathological phenotype of tau transgenic mice. However, whether interfering with leukotrienes biosynthesis is beneficial after the behavioral deficits and the neuropathology have fully developed in these mice is not known. To test this hypothesis, aged tau transgenic mice were randomized to receive zileuton, a specific leukotriene biosynthesis inhibitor, or vehicle starting at 12 months of age for 16 weeks and then assessed in their functional and pathological phenotype. Compared with baseline, we observed that untreated tau mice had a worsening of their memory and spatial learning. By contrast, tau mice treated with zileuton had a reversal of these deficits and behaved in an undistinguishable manner from wild-type mice. Leukotriene-inhibited tau mice had an amelioration of synaptic integrity, lower levels of neuroinflammation, and a significant reduction in tau phosphorylation and pathology, which was secondary to an involvement of the cdk5 kinase pathway. Taken together, our findings represent the first demonstration that the leukotriene biosynthesis is functionally involved at the later stages of the tau pathological phenotype and represents an ideal target with viable therapeutic potential for treating human tauopathies.
 

haidut

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Learning Impairments, Memory Deficits, and Neuropathology in Aged Tau Transgenic Mice Are Dependent on Leukotrienes Biosynthesis: Role of the cdk5 ... - PubMed - NCBI (6/7/2018)

Mol Neurobiol. 2018 Jun 7. doi: 10.1007/s12035-018-1124-7. [Epub ahead of print]
Learning Impairments, Memory Deficits, and Neuropathology in Aged Tau Transgenic Mice Are Dependent on Leukotrienes Biosynthesis: Role of the cdk5 Kinase Pathway.
Giannopoulos PF1, Chiu J1, Praticò D2.
Author information

Abstract
Previous studies showed that the leukotrienes pathway is increased in human tauopathy and that its manipulation may modulate the onset and development of the pathological phenotype of tau transgenic mice. However, whether interfering with leukotrienes biosynthesis is beneficial after the behavioral deficits and the neuropathology have fully developed in these mice is not known. To test this hypothesis, aged tau transgenic mice were randomized to receive zileuton, a specific leukotriene biosynthesis inhibitor, or vehicle starting at 12 months of age for 16 weeks and then assessed in their functional and pathological phenotype. Compared with baseline, we observed that untreated tau mice had a worsening of their memory and spatial learning. By contrast, tau mice treated with zileuton had a reversal of these deficits and behaved in an undistinguishable manner from wild-type mice. Leukotriene-inhibited tau mice had an amelioration of synaptic integrity, lower levels of neuroinflammation, and a significant reduction in tau phosphorylation and pathology, which was secondary to an involvement of the cdk5 kinase pathway. Taken together, our findings represent the first demonstration that the leukotriene biosynthesis is functionally involved at the later stages of the tau pathological phenotype and represents an ideal target with viable therapeutic potential for treating human tauopathies.

Nice, thanks for posting. Vitamin E is one of the good LOX inhibitors that are widely available. I think saturated fats are also capable of inhibiting LOX.
 

rei

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Aug 6, 2017
Messages
1,607
What relation does ketogenic diet have with PUFA? Well going keto will definitely raise the PUFA consumption, but keto in itself doesn't recommend foods filled with PUFA. But when you consume animal meats, eggs, fish, cheese, eggs and the like, PUFA by default will go up quite a bit. Yet despite this, we have a slew of studies above that shows a keto diet in itself helps, protects, and/or reverses all of the above.

Ketones are a very clean and easily utilized fuel for the body. If you have wrecked glucose metabolism due to PUFA then adding in the ketone might easily restore normal energy balance. The brain is obviously the most affected here since it does not burn fat.
 
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