Medical

The "Big Bang" of Alzheimer’s: Breakthrough study uncovers genesis of the disease

The "Big Bang" of Alzheimer’s:...
New insights into the shape of toxic tau proteins before they form neuron-destroying tangles could lead to an early diagnostic method for Alzheimer's 
New insights into the shape of toxic tau proteins before they form neuron-destroying tangles could lead to an early diagnostic method for Alzheimer's 
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New insights into the shape of toxic tau proteins before they form neuron-destroying tangles could lead to an early diagnostic method for Alzheimer's 
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New insights into the shape of toxic tau proteins before they form neuron-destroying tangles could lead to an early diagnostic method for Alzheimer's 

Impressive new research led by scientists at UT Southwestern, has discovered the earliest point in a neurodegenerative process that is thought to lead to dementia. The researchers describe the discovery as like finding the "Big Bang" of Alzheimer's disease, and it's hoped the work leads to new treatments and ways to detect the disease before major symptoms take hold.

"This is perhaps the biggest finding we have made to date," says Marc Diamond, a primary collaborator on this new study, "though it will likely be some time before any benefits materialize in the clinic. This changes much of how we think about the problem."

Much modern Alzheimer's research concentrates on a specific protein called amyloid beta, and the clumping of that protein is suspected as being the primary pathological cause of the disease's symptoms. But, after a long series of clinical trial failures in drugs designed to target those amyloid beta plaques, some scientists are turning their research attentions elsewhere.

This new research focuses on a different protein, called tau. These tau proteins have been found to form abnormal clumps in the brain, called neurofibrillary tangles, which can accumulate and kill neurons. Some researchers hypothesize that this is actually the primary causative source of Alzheimer's disease.

Until now it was not known how, or when, these tau proteins began to accumulate into tangles in the brain. It was previously believed that isolated tau proteins didn't have a distinctly harmful shape until they began to aggregate with other tau proteins. But the new research has revealed that a toxic tau protein actually presents itself as misfolded, exposing parts that are usually folded inside, before it begins to aggregate. It is these exposed parts of the protein that enable aggregation, forming the larger toxic tangles.

"We think of this as the 'Big Bang' of tau pathology," says Diamond. "This is a way of peering to the very beginning of the disease process. It moves us backward to a very discreet point where we see the appearance of the first molecular change that leads to neurodegeneration in Alzheimer's."

From here the research is set to take two different prospective pathways. One will first look at developing a simple diagnostic test to detect signs of this abnormal tau protein, either through a blood test, or less ideally a spinal fluid test. If these toxic tau proteins can be easily detected then clinicians may be able to diagnose Alzheimer's before major degenerative cognitive symptoms take hold.

The second research pathway flowing out of this major discovery involves investigating prospective drug treatments that could interrupt the tau aggregation process. The researchers point to a new drug called tafamidis, as an exciting example of a similar medicine designed to stabilize a protein that can clump and cause adverse symptoms.

Tafamidis was designed to delay impairment to nerve function caused by the toxic aggregation of a normally harmless protein called transthyretin and is currently approved for use in both Europe and Japan. However, the FDA has called for further clinical proof before approving the drug for use in the United States.

Now that this early alteration in the shape of tau molecules has been identified, researchers can more effectively focus on potential drug targets to inhibit the toxic aggregations at this stage.

"The hunt is on to build on this finding and make a treatment that blocks the neurodegeneration process where it begins," says Diamond. "If it works, the incidence of Alzheimer's disease could be substantially reduced. That would be amazing."

The research was published in the journal eLife.

Source: UT Southwestern Medical Center

16 comments
ScienceBetty
The NIH has granted Signum Biosciences a million dollars to start human trials in AD patients. There are many studies already published on this patented supplement. A simple search on Google of “tau and EHT” will give you some information. It’s safe to give to kids. Many former NFL players swear by it to reverse the effects of suspected CTE.
dfmd
Sifting thru the batllefield debris. What then started the guns of the innate immune system firing in the first place? Was it a microbe or a mollicute or a molecular mimic? The soldiers either marched off or were buried long ago. The Big bang simile is cognitive backwash from a marketing MBA and has a mildly demented confabulatory quailty. This article is a plaintive cry for further funding.
john05
Respectfully, tau is NOT the cause of dementia nor is any pharmaceutical the cure. Why is it that we always seem to settle for "treatments" rather than "cures"? If I were to ever suffer from dementia, it would only be because I either didn't supply my body with sufficient nutrients or subjected myself to toxins... or both. It would certainly not be because of a pharmaceutical "deficiency". Let's keep looking until we find the cause of misfolded tau proteins... and then keep asking "why?" until we find the TRUE cause of dementia.
Don Duncan
Well put dfmd! How did medicine go so wrong, be so "treatment of symptoms" orientated? I know this strategy generates the maximum profit but it also generates the maximum harm. What happened to a doctor's oath, "First, do no harm"? And funding? Funding comes from a bureaucracy that accepts this. Why? It's not their money. They have no accountability, e.g., the connection between funding and results is non-existent. The little progress made is in spite of the funding, not because of it. Lack of progress benefits the researchers. If they find a cure, funding stops, if not they may enjoy funded "research" their whole lives. Contrast this against private investment capital that lives or dies by productive results. Yes, that popularly maligned goal, "profit", provides a humanitarian result. That's because profit only comes from success, at least profit not based on force or fraud. Unfortunately, force & fraud are the worldwide popular political paradigm. Voluntary interaction, e.g., capitalism, is potentially evil and therefore needs to be violently controlled? Really? When will that myth be exposed as a dangerous superstition?
Nik
The term, ''prevention is better than a cure,'' looms large. Surely it would be an improvement to find the cause of the tau proteins, rather than trying to fix them afterwards? My guess would be that an invasive agent like a virus, bacteria, or fungus would be responsible. The technique is treating the symptoms, not the cause, but is obviously likely to be far more lucrative for 'Big Pharma,' than a preventative cure.
Observer101
It is interesting that the FDA wants more "testing" before approving a drug in the US, that is already being used in Japan and Europe....WHY IS THAT? I think it is time the FDA should allow "human trials" on patients that VOLUNTEER, knowing that they might die, if they so wish to participate. You see, when you're dying, and there is a POSSIBILITY that an experimental drug might help, it should be YOUR CHOICE, and not the Government. Of course BIG PHARMA might lie to you if you volunteer, just to get you into their programs....
Gerry Lavell
A misfolded protein (called a prion) is not a surprise given the association with CJD. And, Nik, 'bacteria is plural - you should have said, ",,, like a virus, bacterium, or fungus ...".
lwilshier
Funny how years ago they linked aluminium to the development of Alzheimers, we were all told to stop using aluminium pots and pans because they had proved it was a factor in the development of the Alzheimers. Now you don't hear a word about this link, yet they continue to put this toxic metal as an adjuvant in many vaccines so most of the popualation is being given aluminium directly into their bloodstreams and brains, far more than you ever would have absorbed from cooking with it. I read this article and nowhere did it mention aluminium. So it was true before as a major cause of this disease and now is not? The link magically disappeared?
richard20
Its my conclusion from extensive study that Alzheimer's and other degenerative brain diseases are the result of a lifetime of progressive brain damage due mostly to eating the typical American diet. The two major causes are brain cell death from lack of oxygen from clogged arteries to the brain, and brain cell death due to excitotoxins, especially free glutamate (a flavor enhancer added to most processed foods). Symptoms don't show up till the brain is 75% damaged as the brain is good at rerouting around damaged cells. The answer is simple: To unclog one's arteries just follow a plant based diet with no added oils and avoid all corporate foods with ingredients like "spices", "natural flavors", "yeast extract" "modified anything" and other names designed to hide free glutamate (MSG). Avoiding other brain toxins like aluminum, BMAA in seafood, vacinations and pesticides is also important,
Ralf Biernacki
@john05, dfmd: Many proteins misfold occasionally, especially when the genes coding for them are mutated, causing a slightly faulty aminoacid sequence. For the vast majority of proteins, the misfolded variants are useless but harmless. For the tau, unfortunately, the misfolded variants clump, causing disruption to cell function. What the research in this article has established is that the misfolding happens before clumping, so it is not influenced by existing clumps, but directly by a DNA mutation. This mutation may be hereditary, or caused by carcinogens. Aluminum is unlikely to be a root cause, because it only becomes involved in amyloid plaques, which have now been established to be secondary to tau clumps---aluminum plays no part in those. Perhaps amyloid has an affinity to aluminum, but that happens incidentally after the disease is already in progress---aluminum accumulation is a symptom, not a cause. That's why there is no longer much interest in the aluminum connection.