Despite concerted efforts to understand Alzheimer’s disease over the past decades, the disease remains a challenge for researchers and a devastating diagnosis for families. On the surface, we watch the animate light in someone’s eyes slowly dim as they try to grasp at memories that are no longer there. In their brain, a slow buildup of proteins forms amyloid plaques and Tau tangles, which seem linked with decreased neural function. Understanding more about Tau and proteins like it will help us better understand and treat not only Alzheimer’s but many diseases.
Alzheimer’s disease is usually linked with dementia or cognitive decline, challenging doctors to differentiate the disease from the natural consequences of aging. Clinicians work hard to categorize patients to better define the disease itself and to apply appropriate therapies. Identifying new biomarkers to aid in this segmentation will help doctors distinguish Alzheimer’s disease from a healthy brain and differentiate the various stages of the disease. This would improve diagnosis, patient care, and the development of new therapies.
Identifying the early stages of the disease is particularly important for improving patient lives because it offers the potential to slow or stop progression to wider brain dysfunction. With the Tau protein’s ties to neurological dysfunction, being able to identify specific Tau species (proteoforms) may be the key to developing improved biomarkers for early Alzheimer’s disease.
To achieve this, we need to more thoroughly characterize the Tau protein, and new tools that enable the analysis of more proteins or achieve more detailed analysis of specific proteins are essential. Such deep investigation into both the whole proteome and individual proteins will improve our understanding of Alzheimer’s biology. This will lead to better and more precise biomarkers for the disease, but requires a quantum leap in proteomics technology, much like we’ve seen in the field of genomics. We hope the Nautilus platform will provide this quantum leap.
During a recent poster presentation at the Alzheimer’s Association International Conference (AAIC), the world’s largest dementia research forum, we shared preliminary data showing how we can use existing commercial antibodies and the powerful single-molecule analysis of the Nautilus platform to learn more about proteins associated with Alzheimer’s disease. In this case, we used antibodies targeting Tau protein and Tau phospho-proteins to explore the different Tau proteoforms that might exist in a sample.
The Tau protein becomes highly modified in our bodies – it is one of the most post-translationally modified proteins discovered. This makes analysis incredibly challenging because there are hundreds to thousands of possible Tau proteoforms. The proteoform distribution – the complete set of existing proteoforms – is also known to change over time in healthy patients, over the course of disease, over various parts of the body, and possibly over the course of treatment. This incredible complexity highlights how much there is to learn and demonstrates the power of technologies, like the Nautilus platform, that enable us to look deeper into Tau proteoforms and their distribution.
Our goal is to demonstrate that a new approach to proteins and proteoforms can improve human health. To that end, we are studying Tau proteoforms and their link to Alzheimer’s disease in collaboration with Genentech. We hope that the use of single-molecule analysis on the Nautilus platform will increase our understanding of how specific Tau proteoforms are linked to Alzheimer’s disease and that this knowledge can be used to develop better Alzheimer’s diagnostics, treatments, and therapeutics.
While our current collaboration with Genentech is focused on Tau, there are many other proteins hypothesized to be involved in the onset and progression of Alzheimer’s. The Nautilus platform is built to enable deep analysis of Tau and any protein that could be a key biomarker or therapeutic target. Our overall goal is to enable deeper analysis of specific proteins, proteoforms, and whole proteomes. Having access to this kind of deep analysis will revolutionize how we understand the complexities of human proteins and complement other technologies to shape the next 10 years of advancements in how we visualize, measure, and treat disease.
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