Proteomics platform sheds new light on tau’s role in Alzheimer’s

Nautilus provides a ‘James Webb telescope’ for tau protein analysis, enabling a deeper understanding of Alzheimer’s disease biology.

Proteomics, the study of the role of proteins in the body, holds huge potential to impact human health and longevity. It has long been known that the proteome contains the information needed to provide greater insight into diseases like Alzheimer’s, but its complexity means that less than 30% of the proteome is routinely measured by researchers today.

At the recent US HUPO conference, proteomics company Nautilus Biotechnology unveiled new experimental findings from its partnerships with pharma giants Genentech and Amgen that demonstrate the capabilities of its platform to shed new light on the human proteome. Of particular interest to those in longevity circles was the revelation of the platform’s ability to enable “tau proteoform” studies in Alzheimer’s disease research.

Longevity.Technology: Tau is a protein essential for stabilizing the internal structure of neurons in the brain. In Alzheimer’s, tau becomes abnormal and disrupts this internal structure, leading to the formation of “tangles” – biomarkers of the disease that are thought to contribute to cognitive decline. A deeper understanding of tau and its role in Alzheimer’s disease biology could deliver fundamentally new capabilities in the treatment of the devastating condition. We caught up with Nautilus founder and chief scientist Dr Parag Mallick to learn more about the company’s work in this area.

A proteoform describes the many different versions of a particular protein produced in cells. The ability to accurately measure and analyze tau proteoforms could provide important insights into Alzheimer’s disease, but that’s easier said than done.

Will proteomics provide the answers to aging?
Proteomics expert Parag Mallick is founder and CSO of Nautilus Biotechnology.

“In just one sample, there could be thousands of different proteoforms of tau,” explains Mallick. “Being able to know whether a particular tau proteoform or series of proteoforms is present in a sample could provide researchers with important clues about specific patterns of tau and their relevance to the current state of the disease, the likelihood of disease progression, and whether a particular therapy will work with patients with a particular pattern of tau.”

Greater detail and resolution

One of the key breakthroughs recently presented by Nautilus is that its proteome analysis platform has demonstrated the ability to measure, on a per molecule basis, the actual diversity of tau proteoforms in a sample. 

“Measuring individual protein molecules in the way that our platform has shown possible through the findings recently released at US HUPO is extremely difficult and gaining the level of resolution of individual proteins demonstrated in these results simply isn’t possible through existing tools like mass spectrometry,” says Mallick. “We believe this represents a significant breakthrough for future Alzheimer’s disease research. The ability to see this greater level of detail and resolution when it comes to tau proteoforms should help drive a more robust understanding of disease biology, the pathology and progression of disease as well as the therapeutic response of tau-related disorders.”

According to Mallick there are three distinct achievements made by Nautilus that enabled it to make this breakthrough. First, that it has unlocked the ability to immobilize individual protein molecules, which allows it to analyze billions of individual proteins one at a time. Second, that its platform can probe those molecules repeatedly and at different locations, resulting in much greater resolution. And finally, that it has made significant advancements in data analysis and interpretation to be able to harness the massive amounts of data being produced by its platform.

“An apt analogy is the difference between looking at the galaxy from a telescope in your backyard to what one can see from the James Webb telescope in space,” says Mallick. “We believe the vastly higher resolution of tau that our technology can provide will allow researchers to go far beyond simply looking at whether tau is present in a sample and how much there is.”

Wider implications for longevity

Now that Nautilus has demonstrated its capabilities in this type of measurement, Mallick says the company is moving its work forward in related areas.

“We’re continuing to expand on the technological capability of our platform to enable it to be applied to other sample types, such as blood and cerebrospinal fluid,” he says. “And we’re also looking to leverage the platform to enable further investigation into how proteoforms impact the biology of Alzheimer’s disease.”

And, while Alzheimer’s disease and tau are certainly key areas of interest for Nautilus, Mallick is quick to stress that proteomics has a far wider role to play in the longevity field.

“We started with tau, but we believe that the application of this technology will have benefits in targeting a wide range of proteins that are involved with age-related diseases,” he says. “For example, the protein P53, which is implicated in the accrual of DNA damage and is a major area of exploration for the pharmaceutical industry.”

READ MORE: Will proteomics provide the answers to aging and longevity?