A study led by the University of Michigan has uncovered significant insights that could clarify an essential enigma regarding the structure of fibrils involved in Alzheimer’s, Parkinson’s, and various other neurodegenerative disorders.
“We’ve observed these fibril formations in patients’ brains for many years,” commented Ursula Jakob, the senior author of the research. “However, the lingering questions are: What functions do these fibrils serve? What is their significance in disease progression? Most crucially, can we eliminate them if they indeed contribute to these debilitating conditions?”
While the latest discovery does not provide direct answers to those inquiries, it could offer a vital piece of the overall puzzle for scientists striving to unravel the molecular mechanisms underlying these diseases. Jakob emphasized the need for a deeper understanding, particularly in light of the limited treatment options available for Alzheimer’s.
Since 2021, the Food and Drug Administration has green-lighted three new Alzheimer’s medications, but this came after a long gap of 17 years without any new approvals, despite numerous clinical trials (currently, over 100 drug candidates are still being assessed).
“The many failed clinical trials indicate that we’re likely missing crucial components of this puzzle,” noted Jakob, a professor in the U-M Department of Molecular, Cellular, and Developmental Biology. “Thus, our fundamental research and that of many others globally is essential if we ever hope to treat or even eradicate these painful illnesses.”
The mystery density
For quite some time, researchers have been aware that fibrils—tiny strands formed from minuscule units known as amyloid proteins—are linked to multiple neurodegenerative diseases. Yet, significant questions persist regarding how these structures accumulate in the body and the role they play in disease development.
Our comprehension of fibrils is continually advancing as scientists adopt new tools and techniques for a more profound examination of these structures. One such advancement is cryogenic electron microscopy, or cryo-EM.
“This technique is highly advanced,” Jakob explained. “It allows us to observe the detailed structure of these fibrils.”
In 2020, a global team led by researchers from Cambridge used cryo-EM to identify a puzzling substance within fibrils taken from patients with a neurodegenerative disorder known as multiple system atrophy.
The researchers could analyze the fibrils down to their individual amino acid components, yet an unidentified material persisted along the fibrils’ length.
“This substance was located in the center of the fibril, and they were unsure what it was,” Jakob recounted. “They labeled it ‘mystery density.'”
Now, Jakob and her team have demonstrated that this unidentified material might actually be a common biological polymer called polyphosphate.
The findings were published in the journal PLOS Biology.
New science, ancient molecule
Polyphosphate is a molecule present in all living organisms and has been utilized by various life forms throughout evolutionary history, according to Jakob. Laboratory studies by her and other scientists also suggest its potential connections to several neurodegenerative disorders.
For instance, her group found that polyphosphate enhances the stability of fibrils and mitigates their harmful effects on lab-cultured neurons. Other studies have indicated that levels of polyphosphate in the brains of rats diminish with age.
Such findings suggest that polyphosphate could play a protective role against neurodegenerative diseases in humans. However, direct evidence confirming this was previously lacking.
“Experiments conducted in test tubes can provide insights, but which of these findings truly relates to the human body?” Jakob questioned.
The human brain presents a highly intricate environment, and researchers have yet to create an experiment that can definitively clarify the role of polyphosphate within it.
Fortunately, earlier studies have provided scientists with precise 3D models of real human fibrils. By creating computer models of these structures, Jakob and her team were able to simulate interactions with polyphosphate, finding a strong fit for the mystery density.
They further experimented by modifying the fibril structure, changing the neighboring amino acids around the mystery density. These alterations led to a loss of polyphosphate association with the fibrils, along with a reduction in their protective effect against neuronal toxicity.
“Due to the technical challenges, we are unable to extract polyphosphate from patient-derived fibrils, preventing us from definitively confirming it as the mystery density,” Jakob clarified. “Nonetheless, we have strong evidence that suggests the mystery density aligns with polyphosphate.”
Their research implies that maintaining appropriate levels of polyphosphate in the brain might help decelerate the advancement of neurodegenerative diseases. Nevertheless, proving this theory will require significant time and financial investment, and further mysteries are expected to arise in the process.
“We’re only at the beginning stages of this research. It’s a fairly recent realization that additional components exist within these fibrils,” she noted. “These components could either play a significant role or none at all. However, we can only hope to combat these devastating diseases if we piece together the puzzle.”
The National Institutes of Health supported this work, which included collaboration with the Howard Hughes Medical Institute, Manipal Academy of Higher Education, and the University of California, San Francisco.
The study’s lead authors were Pavithra Mahadevan, a graduate student in Jakob’s lab, and Philipp Hüttemann, who conducted the research as an undergraduate at U-M.
