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Dangerous Braids That Tangle in Brains and Veins

The views expressed are those of the author and are not necessarily those of Scientific American.

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Alzheimer’s disease is a neurodegenerative condition of the brain that is assuming epidemic proportions as the population ages, since it can strike almost anyone.

Sickle Cell Disease is a strictly genetic disorder of African origins that rigidifies red blood cells.

These would seem to be worlds apart in more ways than one.

Yet I was reminded this week that one of the delights of science is the discovery of the connections between things that seem totally unrelated:  A recent breakthrough in understanding Alzheimer’s, described in the current Early Edition issue of the Proceedings of the National Academy of Sciences is based on advances my colleagues and I made some 30 years ago in understanding sickle cell.

What these maladies have in common is the association of molecules that were never intended to come together in healthy processes.  When the Alzheimer’s molecule, known as amyloid-β, congregates in the brain, it forms the tangles and plaques that are a well-known visual signature found post-mortem in the brains of those who have suffered from the disease.

Those tangles are a type of molecule known as polymers, which are strings of molecules stuck end to end in an intricate but pathological braid.

Sickle cell too has its deadly braided molecules—this time, of the oxygen carrier hemoglobin.   These long structures distort cells, but more seriously, stiffen them, and impede their vital passage through the circulation.   In both cases, there is a premium on preventing these polymeric strings from initiating.

What turns out to be particularly insidious is that both assemblies can use their surfaces to recruit even more molecules to their pathogenic cause.  Called heterogeneous nucleation, the mechanism entails new polymers spontaneously beginning on the surfaces of old one.

It was this discovery, that I made with colleagues James Hofrichter and William Eaton of the National Institutes of Health (published in 1985), that proved to be the Rosetta Stone for understanding sickle hemoglobin polymerization.  It explained how so many polymers could form so rapidly, and was a process that was previously unknown in the realm of biological polymerization.

This same idea has now been adapted to the formation of Alzheimer’s polymers by Knowles et al. of Cambridge University.  Previous thinking was that those polymers of Aβ somehow snapped, thereby increasing their number.  Knowles et al showed by careful experimentation that when solutions were stirred, fibers indeed broke, but as the stirring was progressively reduced, the hidden process of heterogeneous nucleation emerged.

The two diseases, disparate in manifestation, obey the same fundamental rules.  This is what Biophysics is all about,the discovery of fundamental physical laws that govern the behavior of diverse biological systems.

Image: adapted from: F. A. Ferrone, J. Hofrichter and W. A. Eaton, 1985, “Kinetics of Sickle Hemoglobin Polymerization  II.  A Double Nucleation Mechanism”, J. Mol. Biol.  183: 611-631

Frank Ferrone About the Author: Frank Ferrone is a Professor of Physics and Senior Associate Vice Provost for Research at Drexel University. Trained as a physicist at Manhattan College (BS) and Princeton University (PhD), his interest in Biological Physics began with his doctoral dissertation, and led him to a subsequent postdoctoral Staff Fellowship at the National Institutes of Health. There he began the work with Drs. Hofrichter and Eaton that would unravel the mechanism of sickle cell polymerization. With NIH grant support he has continued exploring various facets of this physically-rich system, and is presently involved in developing diagnostic tools to help describe the state of patients suffering from the disease.

The views expressed are those of the author and are not necessarily those of Scientific American.

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  1. 1. ironjustice 6:49 pm 05/30/2013

    Oxidation , carbonyl induced polymerization , in both diseases. Evidenced in those with Sickle , prevention of crisis , by keeping hemoglobin low.
    “Prevention of sickle cell crises with multiple phlebotomies”

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  2. 2. Miss Carolyn 1:19 pm 06/1/2013

    I had a brother who started having seizures in his 40′s (late 1980s) and was eventually diagnosed with A-V malformation which involves knots of paper-thin blood vessel (arteries & veins) tangles growing together in his brian. He was told that it was a congenital defect. My mother raised $10,000 for the surgeon’s fee for Harvard Medical to perform an experimental (at the time) laser surgery to cauterize as many of the blood vessels as possible to stop the bleeding, seizures and his forestall the possibility of death from hemorrhaging of these thin vessels. They told him that he could sneeze and die from bleeding in the brain (which caused him to suffer great depression). The procedure was successful and he was sent home and put on anti-seizure meds for the rest of his (short) life. A few years later he was diagnosed with leukemia and was under treatment for both conditions (which added to his depression) at the time of his death in 1991 by an auto accident – he was broadsided by a driver who had fallen asleep at the wheel. So we will never know just how successful the surgery was. He had been told by the Harvard docs that his name would go down in their medical history archives because he was the first person to have this type of laser surgery in his brain. His name was Billy Gray. To my knowledge, my family has no history of sickle cell anemia. But leukemia (CLL) has appeared (after age 60) in several of my siblings…3 brothers including Billy, and recently 1 sister has been diagnosed with the precursor for it. My mother and several of her siblings had Alzheimer’s at their death. All of whom lived to be 85+. My mother ceased being independent around 85 years of age. And died at age 93. I am a 65 year, old African American female. I and concerned that I will contract Alzhiemer’s. I hope this information can be of possible help to researchers of Sickle cell, Alz and other such conditions.

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  3. 3. Miss Carolyn 1:24 pm 06/1/2013

    Atherosclerosis also runs in my family.

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  4. 4. ironjustice 8:19 pm 06/1/2013

    Another example of iron induced polymerization

    “We study the effects of certain amphiphilic substances on the iron- and thrombin-induced fibrinogen polymerization visualized using scanning electron microscopy. We argue that the culprit is an excessive accumulation of free iron in blood, known to be associated with CVD”

    The theory is , iron preceding the polymerization in Sickle Cell , iron before Sickle manifests , evidenced by a cassava diet , high in metal binding thiocyanate which ameliorates Sickle Cell and low iron diet too , ameliorates Sickle Cell.

    “Cyanates can control the sickle cell crisis. Thiocyanate is thought to be the active molecule that helps people with sickle-shaped Red Blood Cells.”

    Low iron prevents Sickle Cell.
    “Overt iron deficiency lowers the MCHC-S and thereby decreases the sickling tendency and the severity of hemolysis. The clinical improvement in SCA following the induction of iron deficient erythropoiesis by repeated phlebotomies or by erythrocytapheresis has been reported.”

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