Increased Cholesterol Esterification As A Cause Of Alzheimer Disease (AD)

haidut

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Peat's most recent newsletter was on the topic of cholesterol and its increased esterification as a possible cause of the many pathologies that occur with aging.
Nov 2018: Dr. Peat Talks About Cholesterol Esters Causing Aging
One of the organs most vulnerable to cholesterol esterification is the brain, as it accumulates more cholesterol than any other organs. One of the most common brain pathologies of old age is dementia, the most widely known form of which is AD. The official cause of AD is of course considered "unknown" but the main hypothesis over the last 20 years has been that it is caused by accumulation of beta-amyloid and tau proteins in the brain. Well, over the last 20 years every single drug targeting beta-amyloid or tau in the brain has failed miserably.
Since 2002, 99%+ of Alzheimer Disease trials have failed

I guess hundreds of billions of wasted money is becoming a bit too much even for Big Pharma. So, when everything else fails, medicine seems to finally start following the metabolic link in AD. The study below states that the accumulation of cholesterol esters precedes the accumulation of both beta-amyloid and tau, and in fact these proteins may not be pathological at all but simply an attempt at removing the cholesterol esters. Yet another example of "evil" spirits lurking in the body and trying to destroy us turning out to be benign attempts at protection/recovery. Now, this is really not anything new. It has been known for decades that beta-amyloid protects people with MS from deterioration and there are many animal experiments showing that administering beta-amyloid is therapeutic for conditions like MS and even ALS.
MS Symptoms Eased by Way Nicotine and Beta-amyloid Work on Immune System, Study Reports

Unfortunately, there is too much money involved in the "amyloid hypothesis" as a villain, so the charade will probably continue for a while until they find a way to reduce BOTH cholesterol esters and beta-amyloid and then announce triumphant victory and ascribe the cure to removing beta-amyloid. Something similar is already under way in prostate cancer treatment, where they will now start giving men testosterone or DHT injections while also continuing to chemically castrate them, and when the cancer disappears the story will be that castration "just works"!
Anyways, I guess a cure is better than no cure even if it is accompanied by widespread fraud. Yet, even the study below does not go far enough and ask why are cholesterol esters increasing with age. Maybe somebody should give these "experts" Peat's email. Or feed them some thyroid so that they may come up with the answer themselves :):

https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(18)30603-9
Untangling Tau: Researchers Find a “Druggable Target” for Treating Alzheimer’s Disease

"...Using induced pluripotent stem cell-derived (iPSC) neurons from AD patients, the researchers report that cholesteryl esters (CE) — the storage product for excess cholesterol within cells — act as regulators of tau. Importantly, through screening of more than 1,600 Food and Drug Administration-approved drugs they found that low doses of the anti-HIV drug efavirenz lowered CE through activation of the neuronal enzyme “CYP46A1”, thereby reducing tau in the AD-patient neurons."

"...Preventing or eliminating the accumulation of Aβ plaques, particularly in the early stages of AD development, has long been the focus of massive scientific efforts and numerous pharmaceutical trials, but these efforts have not yet resulted in effective and approved therapies for AD. Currently, the only approved therapies for AD manage behavioral symptoms, but do not slow or delay disease progression. There is no cure yet."

"...In the new research, Goldstein, with co-first authors Vanessa Langness, a PhD graduate student in Goldstein’s lab, and Rik van der Kant, PhD, a senior scientist at Vrije University in Amsterdam and former postdoctoral fellow in Goldstein’s lab, used iPSC-derived neurons from AD patients to create cellular models of the disease, both familial and sporadic types. They found that CE are upstream of both Aβ and tau, thus providing a target that could prevent the abnormal build-up of both proteins simultaneously. In addition, they discovered that CE prompts build-up of Tau even in the absence of Aβ, indicating that simply removing Aβ from the brain — the goal of many AD drug development efforts — would not be sufficient to stop the disease."
 

GAF

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We need some more expertise on Lipase. See wolman disease/CESD. Lysosomal Acid Lipase. Attached is a pdf on Hormone Sensitive Lipase that I found interesting.

Without Lipase your cholesterol esters do not convert back to free cholesterol and your body accumulates esters in all the wrong places and then you die.
 

Attachments

  • Hormone Sensitive Lipase.pdf
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aguilaroja

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Nov 2018: Dr. Peat Talks About Cholesterol Esters Causing Aging
One of the organs most vulnerable to cholesterol esterification is the brain, as it accumulates more cholesterol than any other organs.
...CE prompts build-up of Tau even in the absence of Aβ, indicating that simply removing Aβ from the brain — the goal of many AD drug development efforts — would not be sufficient to stop the disease."
Two recent papers, less specific but suggestive in the same direction are linked below. AFAIK they were not mentioned in Dr. Peat's recent newsletters, nor in the helpful threads by @ecstatichamster and others.

Thematic Review Series: ApoE and Lipid Homeostasis in Alzheimer’s Disease: Cellular cholesterol homeostasis and Alzheimer’s disease
"Regarding the CE [Cholesterol esters] levels in mouse and human brains, in normal states, the values are very low, making up less than 1% of the free unesterified cholesterol. However, in the vulnerable (entorhinal cortex) regions of brain samples from AD [Alzheimer's disease] patients, CE levels increase by 1.8-fold (215). In the brains of three different AD mouse models (that express mutant human APP [amyloid precursor protein] or mutant APP and mutant presenilin 1), the CE levels rose to values 3- to 11-fold higher than those in the control mice "

The level of 24-Hydroxycholesteryl Esters is an Early Marker of Alzheimer's Disease. - PubMed - NCBI
"the reduction of % 24OH-CE[Cholesterol esters] in AD [Alzheimer's disease] and MCI [mild cognitive impairment] conv[converting to]-AD, as well as the anticipation of the disease in patients with the lowest % 24OH-CE, support a role of the cholesterol/lecithin-cholesterol acyltransferase axis in AD onset/progression."
 

haidut

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Two recent papers, less specific but suggestive in the same direction are linked below. AFAIK they were not mentioned in Dr. Peat's recent newsletters, nor in the helpful threads by @ecstatichamster and others.

Thematic Review Series: ApoE and Lipid Homeostasis in Alzheimer’s Disease: Cellular cholesterol homeostasis and Alzheimer’s disease
"Regarding the CE [Cholesterol esters] levels in mouse and human brains, in normal states, the values are very low, making up less than 1% of the free unesterified cholesterol. However, in the vulnerable (entorhinal cortex) regions of brain samples from AD [Alzheimer's disease] patients, CE levels increase by 1.8-fold (215). In the brains of three different AD mouse models (that express mutant human APP [amyloid precursor protein] or mutant APP and mutant presenilin 1), the CE levels rose to values 3- to 11-fold higher than those in the control mice "

The level of 24-Hydroxycholesteryl Esters is an Early Marker of Alzheimer's Disease. - PubMed - NCBI
"the reduction of % 24OH-CE[Cholesterol esters] in AD [Alzheimer's disease] and MCI [mild cognitive impairment] conv[converting to]-AD, as well as the anticipation of the disease in patients with the lowest % 24OH-CE, support a role of the cholesterol/lecithin-cholesterol acyltransferase axis in AD onset/progression."

Thanks, good links. Glad to see there is more attention given to lipid dysfunction in the brain. I would love to see a study asking why this accumulation occurs to start with, which will probably lead to questions about metabolism, thyroid, endocrine dysfunction, etc.
 

Texon

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Joined
Nov 28, 2016
Messages
431
Peat's most recent newsletter was on the topic of cholesterol and its increased esterification as a possible cause of the many pathologies that occur with aging.
Nov 2018: Dr. Peat Talks About Cholesterol Esters Causing Aging
One of the organs most vulnerable to cholesterol esterification is the brain, as it accumulates more cholesterol than any other organs. One of the most common brain pathologies of old age is dementia, the most widely known form of which is AD. The official cause of AD is of course considered "unknown" but the main hypothesis over the last 20 years has been that it is caused by accumulation of beta-amyloid and tau proteins in the brain. Well, over the last 20 years every single drug targeting beta-amyloid or tau in the brain has failed miserably.
Since 2002, 99%+ of Alzheimer Disease trials have failed

I guess hundreds of billions of wasted money is becoming a bit too much even for Big Pharma. So, when everything else fails, medicine seems to finally start following the metabolic link in AD. The study below states that the accumulation of cholesterol esters precedes the accumulation of both beta-amyloid and tau, and in fact these proteins may not be pathological at all but simply an attempt at removing the cholesterol esters. Yet another example of "evil" spirits lurking in the body and trying to destroy us turning out to be benign attempts at protection/recovery. Now, this is really not anything new. It has been known for decades that beta-amyloid protects people with MS from deterioration and there are many animal experiments showing that administering beta-amyloid is therapeutic for conditions like MS and even ALS.
MS Symptoms Eased by Way Nicotine and Beta-amyloid Work on Immune System, Study Reports

Unfortunately, there is too much money involved in the "amyloid hypothesis" as a villain, so the charade will probably continue for a while until they find a way to reduce BOTH cholesterol esters and beta-amyloid and then announce triumphant victory and ascribe the cure to removing beta-amyloid. Something similar is already under way in prostate cancer treatment, where they will now start giving men testosterone or DHT injections while also continuing to chemically castrate them, and when the cancer disappears the story will be that castration "just works"!
Anyways, I guess a cure is better than no cure even if it is accompanied by widespread fraud. Yet, even the study below does not go far enough and ask why are cholesterol esters increasing with age. Maybe somebody should give these "experts" Peat's email. Or feed them some thyroid so that they may come up with the answer themselves :):

https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(18)30603-9
Untangling Tau: Researchers Find a “Druggable Target” for Treating Alzheimer’s Disease

"...Using induced pluripotent stem cell-derived (iPSC) neurons from AD patients, the researchers report that cholesteryl esters (CE) — the storage product for excess cholesterol within cells — act as regulators of tau. Importantly, through screening of more than 1,600 Food and Drug Administration-approved drugs they found that low doses of the anti-HIV drug efavirenz lowered CE through activation of the neuronal enzyme “CYP46A1”, thereby reducing tau in the AD-patient neurons."

"...Preventing or eliminating the accumulation of Aβ plaques, particularly in the early stages of AD development, has long been the focus of massive scientific efforts and numerous pharmaceutical trials, but these efforts have not yet resulted in effective and approved therapies for AD. Currently, the only approved therapies for AD manage behavioral symptoms, but do not slow or delay disease progression. There is no cure yet."

"...In the new research, Goldstein, with co-first authors Vanessa Langness, a PhD graduate student in Goldstein’s lab, and Rik van der Kant, PhD, a senior scientist at Vrije University in Amsterdam and former postdoctoral fellow in Goldstein’s lab, used iPSC-derived neurons from AD patients to create cellular models of the disease, both familial and sporadic types. They found that CE are upstream of both Aβ and tau, thus providing a target that could prevent the abnormal build-up of both proteins simultaneously. In addition, they discovered that CE prompts build-up of Tau even in the absence of Aβ, indicating that simply removing Aβ from the brain — the goal of many AD drug development efforts — would not be sufficient to stop the disease."

Haidut I just stumbled onto this yesterday, looks like a very possible cure. The website is run by parents on behalf of their kids with a genetic defect inherited from their parents, associated with impaired serine metabolism. The videos present the discovery, I.e. toxic bmaa molecules crowding out and replacing serine in nerve sheathing.
L-Serine and Fibromyalgia, Peripheral Neuropathy, 3-PGDH, ALS | The Serine Store
 

skominac

Member
Joined
Jul 25, 2013
Messages
228
Yeah, I was just going to say: have you guys not heard that one primary cause of ALS and AD is a toxin that mimics amino acid Serine and injects itself into the protein as such, causing the protein to unfold into tangle? So, in this case, Serine can prevent that since it's a better match, but can also displace the toxin to some degree. I think this is great discovery, though I suspect there could be some other causes of protein misfolding.
 
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