Science at its very best informs and intrigues. I have been lucky. My scientific life has been a continuum of discoveries, many of which remained just that, unexplained observations of life and living. One such highlight of a varied scientific career was the discovery of spherulites made of protein and specifically the amyloid beta protein implicated in the aetiology of Alzheimer’s disease. I was working with my friend and long time collaborator Joanna Collingwood. We were both interested in metals in brain tissue in neurodegenerative disease and while imaging metal distribution in brain tissue using synchrotron X-ray fluorescence Jo brought to my attention a proliferation of protein-like spherical structures in hippocampal tissue in Alzheimer’s disease. Further investigation of these unusual structures revealed some intriguing optical properties not least of which being their appearance as Maltese crosses when viewed under cross polarised light. See ‘g’ in the figure below. For a full description of this figure and other figures presented herein please read the published paper.
We used Congo red staining and other complementary methods to tentatively identify the structures as being composed of amyloid and probably amyloid beta protein. Intriguingly, similar structures bearing the Maltese cross signature had previously been identified in amyloid aggregates of insulin by the physicist Athene Donald. She called these structures spherulites. I contacted Athene to share with her our observations and this led to a fruitful collaboration over the following years.
I was keen to understand if the spherulites we observed in Alzheimer’s disease tissue were composed of amyloid beta protein and might be formed in in vitro preparations of the protein. The results were astonishing and bewildering and resulted in me spending many hours looking into the darkness of amyloid beta preparations viewed under cross polarised light. Hence the title of this post, I was looking for spherulites (stars) in darkness, jewels of protein in a starry, starry night. I looked for so long and so hard that I swear I used to see spherulites in the night sky as I rode home on my bike. I found the first spherulites of amyloid beta protein in an in vitro preparation of the protein. I present the evidence in the figure below.
This was an exciting time. Not only had I made and observed spherulites of amyloid beta protein in vitro but I was able to demonstrate that many of these protein structures had a ‘mineral’ core. You can see the star-shaped mineral core in images of individual spherulites in the figure above.
The fascinating discovery of spherulites of amyloid beta protein in vitro and in vivo asked one very direct question. Were spherulites and senile plaques found in brain tissue in Alzheimer’s disease one and the same thing. If so then why had they not been identified as such in previous research. Well, perhaps they had since one earlier study had shown that senile plaques gave a Maltese cross signature under partially polarised light. Another potentially important reason why senile plaques had not been identified as spherulites in previous research is related to their size and how brain tissue sections are usually prepared for microscopy. Mature, fully formed senile plaques are typically identified in 5 micron thick tissue sections as being about 20 microns in diameter. If what is usually observed in tissue just 5 microns thick is only a thin section across a senile plaque then this is what will be seen. We made our observation of spherulites in Alzheimer’s disease tissue that had been processed for the synchrotron and was 30 or 40 microns in thickness. So, the likelihood of capturing whole or near complete spherical structures typically 20 microns in diameter is substantially greater and this was reflected in the number of structures we observed that displayed the classical Maltese cross configuration of a spherulite.
We went on to test our contention that mature, fully formed senile plaques (known to have a mineral core) are spherulites. We published our results and waited for others to confirm and/or refute our findings. We are, of course, still waiting. Early research on senile plaques consistently showed the presence of a mineral core. Our recent research on familial Alzheimer’s disease showed unequivocally the intimate relationship between aluminium and senile plaques. I tried very hard to continue our research on spherulites in brain tissue in Alzheimer’s disease. We were unable to obtain funding. Now that I can, I will stick my neck out and say that mature senile plaques and spherulites are one and the same. One way or another spherulites are a beautiful addition to the starry, starry night of cross polarised microscopy of amyloid beta protein.
Thank you for continuing your scientific search. I would very much like your work to reach a wider audience, especially since Walter Chestnut (see his substack) is also been working on the same, however he is positing that the contributing factor is the spike protein damage causing the increased rates of amyloid proteins. Despite me pointing out very early on, partially through your work, that amyloid proteins have been with us, and increasing for decades.
I'm sure the recent addition of spike proteins are contributing to a specific increase, simply by their toxic nature and the bodies mechanism of creating amyloid as a way to limit damage in critical areas- like partitioning in a damaged submarine so to speak. But your work on aluminium shows that the problem has been around much, much longer in our environment and lifestyles. Which is the real problem. Walter's work is significant (And excuse my bluntness, he has a wider audience here on substack), but YOUR work is crucial and needs to get out to the wider world!
😊 thank you for doggedly pursuing the science and for all your sacrifice in doing so.🙏🙏🙏🙏🙏🙏🙏🙏
Yes, the metal leads to the amyloid, but still these scientists obsesses over amyloid as the issue.
It's like eating spoiled food, getting diarrhea, and then they study the diahrrea as the cause of your dehydration caused sickness... 🤦♂️