New Molecule Destroys Alzheimer’s-Causing Amyloid Tangles

Alzheimer's Losing Brain

The green tea molecule, known as EGCG, is known to break up tau fibers, which are lengthy, multilayered filaments that create tangles that target neurons and cause them to die.

A molecule found in green tea helped UCLA biochemists in the discovery of multiple molecules capable of destroying tau fibers.

University of California, Los Angeles (UCLA) researchers used a molecule present in green tea to uncover more molecules that may break up protein tangles in the brain, which are known to cause Alzheimer’s disease and other disorders.

Tau fibers, which are lengthy, multilayered filaments that create tangles and attack neurons, are known to be broken up by the green tea molecule EGCG.

UCLA biochemists detail how EGCG breaks tau fibers layer by layer in a paper that was recently published in the journal Nature Communications. They also describe how they found other compounds that are likely to function in the same manner and might be better potential candidates for drugs than EGCG, which has difficulty penetrating the brain. The discovery offers up new possibilities for treating Alzheimer’s, Parkinson’s, and other neurodegenerative diseases by developing drugs that target the structure of tau fibers and other amyloid fibrils.

Thousands of J-shaped layers of tau molecules joined together form the type of amyloid fibrils known as tangles, which were originally identified in the post-mortem brain of a dementia patient by Alois Alzheimer a century ago. As these fibers grow and spread throughout the brain, they kill neurons and cause brain atrophy. Many researchers believe that the removal or destruction of tau fibers can slow the progression of dementia.

“If we could break up these fibers we may be able to stop the death of neurons,” said David Eisenberg, UCLA professor of chemistry and biochemistry whose lab led the new research. “Industry has generally failed at doing this because they mainly used large antibodies that have difficulty getting into the brain. For a couple of decades, scientists have known there’s a molecule in green tea called EGCG that can break up amyloid fibers, and that’s where our work departs from the rest.”

EGCG has been studied extensively but has never worked as a drug for Alzheimer’s because its ability to dismantle tau fibers works best in water, and it doesn’t enter cells or the brain easily. Also, as soon as EGCG enters the bloodstream it binds to many proteins besides tau fibers, weakening its efficacy.

To investigate the mechanisms through which EGCG breaks up tau fibers, the researchers extracted tau tangles from the brains of people who died from Alzheimer’s and incubated them for varying amounts of time with EGCG. Within three hours, half the fibers were gone and those that remained were partially degraded. After 24 hours, all the fibers had disappeared.

Fibrils in the middle stage of EGCG-induced degradation were flash-frozen, and images of these frozen samples showed how EGCG snapped the fibrils into apparently harmless pieces.

“The EGCG molecules bind to each layer of the fibers, but the molecules want to be closer together. As they move together the fiber snaps,” Eisenberg said.

Kevin Murray, who was a UCLA doctoral student at the time and is now in the neurology department at Brown University, identified specific locations, called pharmacophores, on the tau fiber to which EGCG molecules are attached. Then he ran computer simulations on a library of 60,000 brain and nervous system-friendly small molecules with the potential to bind to the same sites. He found several hundred molecules that were 25 atoms or less in size, all with the potential to bind even better to the tau fiber pharmacophores. Experiments with the top candidate molecules identified from the computational screening identified about a half dozen that broke up the tau fibers.

“Using the super-computing resources available at UCLA, we are able to screen vast libraries of drugs virtually before any wet-lab experiments are required,” Murray said.

A few of these top compounds, most notably molecules called CNS-11 and CNS-17, also stopped the fibers from spreading from cell to cell. The authors think these molecules are candidates for drugs that could be developed to treat Alzheimer’s disease.

“For cancer and many metabolic diseases knowing the structure of the disease-causing protein has led to effective drugs that halt the disease-causing action,” Eisenberg said. “But it’s only recently that scientists learned the structures of tau tangles. We’ve now identified small molecules that break up these fibers. The bottom line is, we’ve put Alzheimer’s disease and amyloid diseases in general on the same basis as cancer, namely, that structure can be used to find drugs.”

CNS-11 is not a drug yet but the authors call it a lead.

“By studying variations of this, which we are doing, we may go from this lead into something that would be a really good drug,” Eisenberg said.

Reference: “Structure-based discovery of small molecules that disaggregate Alzheimer’s disease tissue derived tau fibrils in vitro” by Paul M. Seidler, Kevin A. Murray, David R. Boyer, Peng Ge, Michael R. Sawaya, Carolyn J. Hu, Xinyi Cheng, Romany Abskharon, Hope Pan, Michael A. DeTure, Christopher K. Williams, Dennis W. Dickson, Harry V. Vinters and David S. Eisenberg, 16 September 2022, Nature Communications.
DOI: 10.1038/s41467-022-32951-4

The study was funded by the National Institutes of Health’s Institute of Aging and the Howard Hughes Medical Institute.

14 Comments on "New Molecule Destroys Alzheimer’s-Causing Amyloid Tangles"

  1. This is great news. I look up Alzheimer’s news everyday. My mom has early on set. She was officially diagnosed at 63, the age she is now, not sure how long she has signs. I hope and hope and hope she may be a recipient of a treatment to stop it and potentially reverse it. I am sure a combination of treatments and therapies would be needed. I wonder if a treatment utilizing these molecules along with stem cells would be helpful, hand in hand? Anyway, nice article to read. I hope something great develops from this that all of those suffering for Alzheimer’s, in any stage, can benefit from.

  2. I’m not sure it’s possible to say Tau is the cause of Alzheimers, that seems to be an oversimplification. Beta amyloid has been targeted for ages with no success, maybe a combined treatment is what is needed, but these plaques are a feature of alzheimers, not necessarily the direct cause.

  3. My daughter is 33 years old. Diagnosed in 2020 with Early Onset Alzheimer’s. Inherited by her father the PSEN-1. The gene was “ turned on” following a vehicle accident. Looking for ANY help! Please!

    • So sorry to hear this. My sister has early onset. I did not understand before that the gene could be switched on like this by trauma. Thank you for sharing this. It helps to understand which is so difficult. I am so sorry for you to go through this with your daughter. I wish you all the best and pray for an answer soon.

    • Hi Lisa,
      These are natural remedies that should help your daughter:
      – sleep – let her sleep as much as she needs, even if she just took a nap 20 mins ago. Sleep is when the brain recovers.
      – coconut water – coconut water is known for its hydrating abilities but it also has healthy fats which the brain needs.
      – eat foods with healthy fats such as home-made mayo, salmon (twice a week) and pistachio ice cream.
      – freshly made watermelon and orange juices – watermelon because it is packed with nutrients and orange because of vitamin C.
      – deep breathing exercises.

  4. Simon makes a great point here. There was another recent study that talked about the oversights made by assuming the tangles are the cause. Some studies untangling them have not yielded improvements.the study posited that a water soluable version of (if memory serves me) the amyloid protein goes down as the beta amyloid goes up and that it may be the lack of this water-soluble amyloid rather than the increase of the other that is causing the trouble, and the tangles may be the result or the symptom not the cause of the trouble. In any case it does seem some great new strides have been made in research.Hopefuly all these researchers are in touch with each other. It will be such a great day for all when our loved ones can be saved from this debilitating disease.

  5. Seems that olfactory nerve bacterial infection via the nose may be a possible cause of dementia and Alzheimers. In mouse models, bacterial infection through the olfactory nerve, then up into the brain showed amyloid plaques being formed in response to the infection. Studies are now focusing on human models and studying whether this is also possible in humans.

  6. Someone didn’t get the memo about beta amyloids. This is just a continuation of funding-science

  7. did an AI or human write this article? Many false assertions made here. I’ll debunk a couple:
    1) “protein tangles in the brain, which are known to cause Alzheimer’s disease and other disorders”
    this is known as the amyloid hypothesis, which is not proven to cause Alzheimer’s in may just be a symptom of an underlying cause
    2)”“If we could break up these fibers we may be able to stop the death of neurons,” said David Eisenberg, UCLA professor of chemistry and biochemistry whose lab led the new research. “Industry has generally failed at doing this because they mainly used large antibodies that have difficulty getting into the brain.”
    Not true about antibodies failing. The antibody Aduhelm definitely got into patient’s brains and reduced amyloid levels by over 50% in just 18 months. But there is no fear clinical benefit which cast out on the amyloid hypothesis.

  8. If blueberries (antioxidants) have been proven to be one of the few things able to cross the blood-brain barrier, couldn’t they serve as the transport into the brain for these, “fiber busting” elements. “The blue bullet”? Total layperson here. Or, sublingual drops (like melatonin) to get, “best shot” blueberry cocktail to the brain, verses, systemic degradation? Lastly, is there a way to use, “neutralized rabies” as the transport to the brain? Sort of like vaccine neutralized…

    Just “brain” storming… Get it?

    Think out of the box. Sometimes I think Big Pharma is way too close the the tree to see the woods.

    Hope this magically slurs some thoughts on “how to cross the blood brain barrier”.

  9. Can they travel to the brain via the nose and inject EGCG into tangles with tiny needles? Repeated treatments?

  10. Green tea nose wash? Lol

  11. What if they inject the molecule into the spinal fluid ?

  12. It probably needs a direct path to the brain. I’m no expert but seems psilocybin mushroom goes directly to the brain and amplifies awareness. Why not attach it to something that seems to stimulate the brain

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