Dangerous Braids That Tangle in Brains and Veins

Frank Ferrone
Dangerous Braids That Tangle in Brains and Veins

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-?, 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 A? 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

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