PUFA/endotoxin cause Alzheimer Disease (AD), the plaques beta-amyloid/tau are protective
-
One of the biggest failures of medicine to date is prevention and treatment of AD. As I posted a decade ago, 99%+ of all AD clinical trials over the last 20+ years have miserably failed. All those failed drugs have targeted one or both of the purported main causes of AD – the beta-amyloid and tau proteins, accumulating in the brains of AD patients.
https://www.bbc.com/news/health-28125265
Worse, the situation with preventing/treating AD has deteriorated so much more over those last 10 years that the latest AD drug (also targeting beta-amyloid/tau accumulation) approved by the FDA triggered the resignation of three (3) members of the drug approval board who thought that the drug is utterly ineffective and only getting approved as a “cash cow” for the pharma company running the trials with it.
In other words, ALL attempts to prevent or treat AD by targeting the beta-amyloid and/or tau plaques in the brains of AD patients have completely failed. As a result, a reasonable person would/should conclude that those plaques may not the main driver of AD, and may even be a protective mechanism the brain develops against another factor that actually causes the disease. Also a decade ago, I stumbled across the apparently well-known effects of the beta-amyloid protein (one of the two major proteins in AD plaques) as a powerful, brain-specific anti-oxidant, and an anti-microbial. Considering that the main role of anti-oxidants is protection against lipid peroxidation and reactive oxygen species (ROS), both of which promote each other, as well as the known compromised gut barrier in AD patients (i.e. increased systemic endotoxin) I made the (perhaps simplistic) suggestion in a podcast that the plaques seen in AD are nothing but a (possibly suboptimal) attempt of the brain to protect itself from PUFA and endotoxin/LPS.
https://pubmed.ncbi.nlm.nih.gov/19320465
https://pubmed.ncbi.nlm.nih.gov/12077180
https://pubmed.ncbi.nlm.nih.gov/25415602
https://en.wikipedia.org/wiki/Amyloid_beta
“…The normal function of Aβ is not yet known.[9] Though some animal studies have shown that the absence of Aβ does not lead to any obvious loss of physiological function,[10][11] several potential activities have been discovered for Aβ, including activation of kinase enzymes,[12][13] protection against oxidative stress,[14][15] regulation of cholesterol transport,[16][17] functioning as a transcription factor,[18][19] and anti-microbial activity.”
Now, in a healthy person eating diverse foods, including organ meats, this protective role would be performed by vitamin E. However, vitamin E intake has significantly dropped in “developed” countries and nowadays medicine even warns against taking vitamin E supplements due to this vitamin being linked to several cancers. Of course, those are just shameless lies, and autopsies on humans who died from AD demonstrate drastically reduced levels of vitamin E in the brains of such people. Furthermore, there are multiple animal studies demonstrating preventative and therapeutic effects of vitamin E in AD. So, preventing/treating AD may be as simple as taking vitamin E as a supplement or eating foods rich in that vitamin. Coincidentally, excessive fatty acid oxidation (FAO), lipid peroxidation, and high ROS are hallmarks of other conditions, especially diabetes (as well as cancer). In that context, one could consider AD as a brain-specific form of diabetes type II, and amenable to the same metabolic treatments. Several recent studies have made the same connection and have called on the FDA to reclassify AD as “diabetes of the brain” and allow drugs for diabetes II to be used for AD.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8910482/
https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-minute-is-alzheimers-type-3-diabetes/
While that is a great step in the right direction, the main first-line of therapy for diabetes II is the drug metformin, which happens to be a potent inhibitor of complex I of the electron transport chain (ETC) and as such is likely to drastically increase ROS levels as well as lipid (PUFA) peroxidation. Luckily, the pro-dopamine and anti-serotonin drug bromocriptine has also been approved by the FDA for diabetes II treatment and is a much better choice for both diabetes and AD.
https://en.wikipedia.org/wiki/Bromocriptine
Despite FDA claiming that the mechanism of action for bromocriptine’s benefit in diabetes is unknown, multiple human and animal studies have demonstrated that bromocriptine lowers the levels of free fatty acids in the blood (anti-lipolysis), as well as FAO. With that in mind, niacinamide, thiamine, biotin, aspirin, progesterone, testosterone, DHT, etc all become possible candidates for AD drugs given their effects of inhibiting excessive lipolysis and FAO, promoting the oxidation of glucose, lowering PUFA peroxidation, and opposing both the effects of endotoxin/LPS, as well as its absorption from the gut.
Well, I digressed quite a bit, but I think it is worth it since the digression not only builds the case for AD being a metabolic, lipid/PUFA-driven disease, but also demonstrates that medicine has once again gotten things exactly backwards. The study below not only demonstrated protective effects of the tau protein against ROS, but also demonstrated that its lack can cause serious neurodegenerative changes. Administering a simple anti-oxidant (in this case NAC, which is risky and quite inferior to vitamin E) was able to protect against the ROS in a manner very similar to the tau protein, confirming the role of tau is indeed protective and related to lipid peroxidation, Speaking of lipids, the study opined that the ROS seen in AD can be caused by excessive lipid accumulation (like diabetes), and such accumulation (even when localized by the brain) can itself easily be caused by a low-carb/high-fat diet. Yet another reason to keep the fat intake at bay.
https://www.nature.com/articles/s41593-024-01740-1
“…Excess reactive oxygen species or free radicals (ROS) are a common feature of neurodegenerative diseases like Alzheimer’s disease. A recent study by postdoctoral associate Dr. Lindsey Goodman and Dr. Hugo Bellen, a distinguished service professor in Molecular Biology and Genetics at Baylor College of Medicine, who also holds a Chair in Neurogenetics at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, have discovered an important role for the disease-associated protein, Tau, in mitigating damage to the brain caused by excessive ROS and in promoting healthy aging. The study was recently published in Nature Neuroscience.”
“…There is mounting evidence supporting the notion that our brains have developed multiple neuroprotective strategies to combat ROS-induced oxidative damage. Studies in the past decade by the Bellen Lab and others have found a new neuroprotective mechanism by which glia (non-neuron brain cells) help to protect neurons from these toxic peroxidated lipids. In 2015, the Bellen team discovered that these toxic lipids are exported to neighboring glial cells and sequestered into lipid droplets (LDs) for storage and future energy production. Lipid droplets are evolutionarily conserved organelles employed by many cell types including glia to stockpile lipids and this can be triggered under conditions of cellular stress such as a high-fat diet, inflammation, altered oxygen levels, etc…Lipid droplets play important roles during development, aging, and in neuropathologies. Recent studies have found a growing number of Alzheimer’s disease-risk-associated genes are associated with the formation and function of lipid droplets in the glia, suggesting that defects in this pathway contribute to disease progression.”
“…While previous research has highlighted Tau’s critical functions in neurons, the Bellen team found that endogenous Tau protein is also important in glia. Flies lacking Tau in glia showed signs of degeneration such as progressive motor defects and decreased lifespans. Interestingly, these flies build up peroxidated lipids in their brains and treating them with an antioxidant, N-acetylcysteine amide, can prevent the motor defects caused by Tau loss in glia. “We also found that endogenous Tau in flies is required for glial lipid droplet formation and for protecting against neuronal ROS. Similarly, Tau was required in glial cells obtained from rats and humans to form lipid droplets,” said Dr. Goodman.”
-
@haidut said in PUFA/endotoxin cause Alzheimer Disease (AD), the plaques beta-amyloid/tau are protective:
our brains have developed multiple neuroprotective strategies to combat ROS-induced oxidative damage.
Qouah... What a remarkable construction! Thanks for caring for the presentation. Well-constructed and argumented, with trustful references, even if the link between peroxidation of brain lipids and endotoxin has still to be contextualized, for me (I’ve associated endotoxins = LPS. Not only, sorry).
Let’s say AD is one possibly occurrence of brain diabetes (DT3) and the target will be easier reached.
Good job! -
Fascinating stuff Georgi thanks for sharing. Is there a place where we can find the studies that you have conducted. I'm specifically looking for the study you did on mice with lymphoma treated with niacinamide.
Thanks,
-
Thank you for sharing this interesting new angle. It fits very well with the recent interest in the connection between antibiotics and AD. In the last three years, several large studies looking at the efficacy of antibiotics have been started, and they should probably yield some very interesting results. In the end, it all comes down to your gut and endotoxins.
-
L LucH referenced this topic on
