The physiological relationship between Alzheimer's, Prion Diseases and Type 2 Diabetes.

[NNadir]

One learns something every day.

Currently at my job I'm working with several clients working on Alzheimer's disease using entirely different mechanisms of action (MOA). (This is a good thing, working from several approaches, which may or may not have relationships to one another.)

I'm catching up on my general reading, and I came across this interesting review article, which caught my eye because of the amyloid nature of Alzheimer's: Second Sphere Interactions in Amyloidogenic Diseases Madhuparna Roy, Arnab Kumar Nath, Ishita Pal, and Somdatta Ghosh Dey Chemical Reviews 2022 122 (14), 12132-12206

The first sentence in this article is this, and the first sentence in it is something I never knew:

Human disorders such as Alzheimer’s disease (AD), type 2 diabetes mellitus (T2Dm), dialysis related amyloidosis (DRA), frontotemporal dementia (FTD), Huntington’s disease (HD), multiple system atrophy (MSA), familial amyloid polyneuropathy (FAP), etc., having varied clinical presentations, share one common histopathological feature, which is the formation and deposition of amyloids in different tissues leading to organ dysfunction. (1?4) Hence, these apparently dissimilar pathogenic conditions, unified by this one specific criterion, are grouped under the category of amyloidogenic diseases or amyloidosis. While some of these are exclusively hereditary, some others are mostly sporadic, with a minor proportion of cases occurring due to genetic factors and even fewer are transmissible (i.e., human prion diseases). (5,6) In a few cases, amyloid formation may result from long-term medical treatment, for example, in DRA, which is linked to hemodialysis, injection-localized amyloidosis associated with treatment for type I diabetes and iatrogenic Creutzfeldt–Jakob disease (iCJD). (7,8) The amyloids are typically proteinase resistant, insoluble, unbranched protein fibrils of 7–10 nm diameter and indefinite length. (6,9) They display unique tinctorial properties like showing green birefringence in cross polarized light on staining with Congo red dye and binding to the fluorescent stains thioflavin T and thioflavin S. (10) Although, protein is the major constituent of these fibrils, sulfated glycosaminoglycans and the normal plasma glycoprotein serum amyloid P component (SAP) are invariably present in the amyloid deposits as well, possibly to promote their aggregation, stabilization, and persistence. (11) Earlier, these protein assemblies were defined as being extracellular and strictly disease-associated, but later studies showing the formation of similar fibrils by disease related proteins in vitro or by other proteins under denaturing conditions or for performing certain physiological functions in bacteria, fungi, and higher eukaryotes including humans, led to the abandonment of these requirements. (12,13) However, it is important to note here that most amyloids are in fact pathogenic, with approximately 50 different proteins/peptides being known until date to form such aggregates under disease conditions. (6)...

I had no idea that all of these diseases shared the same physiological basis. Again, if one is lucky and/or diligent, one learns something every day.

Interestingly most of these diseases have onset late in life, which given the commonality, makes sense, because the accumulation of misfolded proteins is a long process.

This review is about second coordination spheres of metals and includes, further down these remarks:

Modifications to the primary sequence of the protein such as by truncation, hyperphosphorylation, etc., are also found to either aid or inhibit the fibrillation process (Figure 1). (30) Particularly for the case of metal ions, especially the biochemically functional metals like Cu, Fe, Zn, etc., any change in their homeostasis and compartmentalization has been found to be enough to influence protein misfolding even in the absence of any external environmental effect as seen in different amyloidogenic diseases. (26) The nonessential and physiologically nonfunctional toxic metals like Hg, Cd, Pb, and Al are also thought to influence these diseases as they are able to access the human body due to possession of certain advantageous characteristics like their biochemically active counterparts, e.g., ionic charge, etc. (31,32) Although the ingestion of the toxic metals is quite low in the gastrointestinal tract, sometimes they are found in excess quantity in the brain and can even interfere with the metabolism process by displacing the original metals from their natural binding site in proteins, giving rise to adverse consequences. (31,33) The multifarious effects of metal coordination include rearrangement of the protein/peptide main chain due to attainment of specific geometries (e.g., Cu(II) binding to ?-2 microglobulin induces a Pro cis–trans isomerization in DRA triggering protein destabilization and consequent self-assembly)...

I added the bold.

The mechanisms of amyloid diseases can be visualized in these two graphics from the paper.



The caption:

Figure 1. Native peptide or protein monomers usually form random-coil structures. However, under the influence of acceleratory factors like aging, mutations, or in the presence of trace metals such as Al, Zn, and Cu, they self-aggregate and oligomerize (dimer to protofibrils) and then convert to insoluble mature amyloid fibrils.

The caption:

Figure 2. Different pathways and associated states of protein/peptide aggregation from a mechanistic and biological perspective. (6)

The chief source in the environment of mercury, cadmium and lead is coal flue gas and coal ash, i.e. dangerous fossil fuel waste. (No Jenny McCarthy and others, the chief source of mercury isn't thimerosal in vaccines; vaccines are trivial sources of mercury exposure.) These three metals are relatively volatile metals and are easily suspended in air. Interestingly coal gets a bye from intellectually impaired people who prattle on insipidly about what is and is not "dangerous."

This may explain why Kentucky elects Senators like Rand Paul and Moscow Mitch, since the neurological impacting amyloid diseases involves these metals.

In our lab we will be monitoring metals in the brain tissue of genetically modified Alzheimer's model mice, although not focusing specifically on toxic metals listed above. I regret we will not be looking at these, but it's not my call.

Interesting, I think.

[bucolic_frolic]

1. Been heavily into these topics from a laymen's standpoint

Relative with mild dementia at one point. Mercury toxic, I would say thimerosal burden is significant for those already toxic.

Lately have been following Dr. Sten Ekburg on Youtube for health explanations. He's heavy on research if only a chiropractor. He puts heavy emphasis on metabolic disease as a factor in many if not most diseases. Everything runs through the liver which is impacted by sugar (which he calls a poison) and its various forms in our modern diet such as high fructose corn syrup.

Decimate the carbs and the weight loss happens.

[NNadir]

4. Concern about thimerosal is nonsense, period.

I personally don't regard the "carb theory" which is, in fact, as old as the hills - my mother was doing it in the 1960s (she died at 51) - as particularly safe, since it often relies on increasing meat consumption which is neither environmentally or physiologically healthy.

There are certainly disadvantages with highly processed foods, but it's not addressed by simplistic thinking.

I don't rely on internet doctors (or chiropractors) for advice on issues of health, but as part of my scientific professional and personal interest, I monitor the primary scientific literature.

In fact, I monitor my doctor's advice in the primary scientific literature. I sometimes disagree with his advice, although he's a fine doctor who I trust implicitly.

For instance we recently disagreed on the matter of controlled release niacin, Niaspan, for which there is some evidence of elevated stroke risk. I reviewed the scientific literature on this topic, and I see where he's coming from, but I still take a niacin supplement OTC based on a risk/benefit analysis, since there is some fairly strong evidence that niacin plays a role in slowing or arresting dementia as well as controlling lipedema. (My work is based on having an active workable mind; I can't afford dementia.)

[bucolic_frolic]

5. When I was mercury burdened, flu shots with thimerasol made me sick for a week

The shot exacerbated all the symptoms. So much so that I went without flu shots for many years until that preservative was removed. Same thing when spray nasal decongestants contained thimerasol.

[NNadir]

6. Again, I rely on the scientific literature, not anecdotal evidence. If one knows about...

...immunology, one knows there are many, many, many reasons that a particular flu vaccine can cause a reaction. A vaccine is designed to elicit a immune response, and often an immune response makes one feel "sick."

I was pretty sick after my first Moderna Covid vaccination. This does not mean that the Moderna vaccine was harmful; it may have very well saved my life.

Thimerosal is a thiosalicylate, structurally related to aspirin but complexed to mercury. It was added to vaccines in a very, very, very, very low concentrations to prevent microbiological contamination.

If one breathes near a coal fired plant, one will easily exceed the dose of mercury that was historically in vaccines.

I am one of the few people here who has worked with thimerosal, while preparing diluents for RIA kits. These were not for consumption but were for assay kits, radioimmunoassay, a historically valuable approach to the measurement of biomarkers in biological matrices such as blood or urine relying on labeling molecules of biological interest with radioactive iodine-125. Thus I have insight to the likely concentrations. They are trivial.

Thimerosal was removed from vaccines not because they represented any significant risk, but because of public hysteria among people unqualified to actually understand reality. To the extent that these people were taken seriously - and there is no rational reason they should have been - we now have things like Polio reappearing in the United States.

Internet reports of "science" are not to be taken seriously without proper critical thinking. This kind of rhetoric can be very harmful. I personally know a young woman, a playmate for my son when they were toddlers, whose mother refused vaccination for her daughter. She's now in her twenties, and my wife and I were hoping against hope that she is safe.

[bucolic_frolic]

7. yes, I realize it is anecdotal, but I was seeing an allergist at the time for mercury

He was one of the original anti-vaxxers who focused on preservatives. This was decades ago.

[live love laugh]

2. Now we need anti-amyloids ... whatever that looks like 🤷🏽‍♀️

[littlemissmartypants]

3. Very interesting read! Thanks for sharing it, NN. ❤

[John ONeill]

8. aluminum

Your source lists aluminum (or aluminium as it's called in this neck of the woods) as one of the 'nonessential and physiologically nonfunctional toxic' metals. I know a lot of Al cookware was thrown out a few years back, but I read that the link was unlikely, so retained my alloy pressure cooker. I use it nearly every day. Should I ?
John O'Neill

[eppur_se_muova]

9. Aluminum is present in traces in most drinking water.

Since many of Earth's rocks are aluminosilicates, water running over rocks can hardly help but pick up some aluminum.

I doubt if the aluminum cookware makes much difference, unless you are cooking lye (which dissolves aluminum).

[NNadir]

11. Looking into the matter, I do see that aluminum, one of the most common elements on Earth...

...is, in fact, neurotoxic, but the effect is mostly notable in people working in the aluminum (or aluminium) industry, and not generally in consumers.

(I downloaded this text: Neurotoxicity of Aluminum and leafed through it.)

An interesting fact I just learned, leafing through this text, is that aluminum passes readily through the blood brain barrier fairly easily, and that in most animals, the concentration in aged subjects tends to exceed the plasma levels; that the transport is more or less irreversible. However, the gastrointestinal transport is low, as are plasma concentrations so generally we do not observe vast toxicity unless - this is still highly speculative - aluminum plays a role in Alzheimer's or at least in some form of Alzheimer's, because I for one, am not convinced that Alzheimer's is just one disease. (I may post an interesting note or two that came in on my JAMA feed recently; it's not clear that the Paisa mutation, E280A -glutamic acid substituting for alanine in the presenilin 1 protein - which nearly always results in early onset senility (generally in the 50s) in a Columbian subpopulation - responds to antibodies directed against amyloid-? deposits. This said, it just may not be a great antibody, crenezumab, and it did not act agains presenilin itself, apparently, but against its product amyloid-?.)

It is known that aluminum appears in tau—tau neurofibrillary tangles, another hallmark of Alzheimer's as well as in amyloid-? plaques. The question is whether, as noted by Eppur Se Muova elsewhere in this thread, whether this is an artifact or a cause. Brain tissue, it seems, always contains some aluminum, but not all brains show Alzheimer's morphological changes. In particular, the inflammasome theory of Alzheimer's (or one or more of Alzheimer's diseases) relies on higher transport across the blood brain barrier. It may just be that the opening of pores from the disease lets more aluminum in; we just don't know.

The most common form of aluminum to which we are exposed is alumina, in both environmental and technical settings, Al2O3. It is this coating, an oxide passivation layer, that makes aluminum stable; highly polished aluminum with the oxide layer removed is pyrophoric. Alumina is amphoteric; it is insoluble at neutral pH, but can dissolve in strong acid or in strong base. I've done both of these reactions myself. The metal is also amphoteric; it will release hydrogen both in acid or in base; it's long been discussed in the hydrogen storage fantasy that never dies.

I have never used a pressure cooker, or if I did, I don't remember doing so. I looked to see at what temperatures they operate. It looks to be about 125°C. Water in the liquid state at 25°C has a pH of around 7, but it changes with temperature. Subcritical water is probably acidic, and supercritical water is definitely acidic, with a pH of around 3. Water is supercritical at 373°C, which is far from 125°C. I don't think the steam in a pressure cooker is acidic enough to seriously impact the dissolution of alumina; 125°C certainly doesn't even qualify as "subcritical."

Personally, I wouldn't worry about it. I'm not an expert in Alzheimer's - I'm more of a dilettante - but I have no fear of aluminum utensils, cans, etc. Other stuff will get me first.

[eppur_se_muova]

10. Are all the pathways in Fig. 2 well established, or is there some speculation in there ?

I realize some hypothesizing is necessary, but am just curious as to whether it's really known to be quite so complicated. When I see four pathways all leading to mature fibrils, it just makes me go 'hmmm' on general principles, like 'too many explanations'.

I've always wondered whether Al really triggers misfolding, or whether the amyloids have the property of being good complexants for Al, in which case the accumulation of Al would be a symptom, not a cause (assuming the accumulation of plaques is kinetically slow, albeit thermodynamically favored).

This strikes me as a well-written article, despite the inherent complexity of its subject and even some unfamiliar terminology. Will have to peruse the original article, and maybe even some footnotes therein, although this is well outside my area of expertise.