It Takes Tau to Tangle
Consider for a moment the constellation of thoughts and experiences that make you who you are – your memories, your intelligence, your talents, even the simple ability to recognize the people you love. You can access that information at any time, without even knowing that you’re doing it. Now imagine those fundamental building blocks of your personality being chipped away—that’s life with Alzheimer’s disease (AD).
AD is associated with two key pathological hallmarks in the brain: plaques made up of a protein called amyloid-beta (Aβ), and neurofibrillary tangles formed due to aggregation of a protein called tau. Both of these contribute to the loss of communication between neurons and subsequent cognitive impairment seen in AD, and both are attractive targets for therapy.
As Genentech neuroscientist Gai Ayalon explains, “Developing therapeutics to stop the formation and spread of plaques and tangles could help slow or even halt the progression of Alzheimer’s disease and have a major impact on the quality of people’s lives.”
To date, the most intensive efforts in developing treatments for AD have focused on amyloid-beta. Promising recent data based on this approach – including our work in partnership with AC Immune – suggest this is an important step in the right direction. But amyloid-beta is only one part of the story. We also need to address tangles, which requires both a deep understanding of tau and focused efforts to find the best therapeutic approach.
Putting Our Brains Together
By Patrick Bigot, Vice President, Head of Alliance Management at Genentech
We’re always in pursuit of the best science from around the world. That’s why, in 2006, we entered into an exclusive research collaboration with the Swiss-based biotechnology company AC Immune to develop therapeutic antibodies that target amyloid-beta for Alzheimer’s disease (AD) and other neurodegenerative disorders. It turned out to be one of our strongest working relationships based on a mutual love of following the science.
The success of this partnership and our combined commitment to finding solutions for people with neurodegenerative disorders led to the agreement of a second research collaboration with AC Immune in 2012 to develop antibody technologies that target the tau protein. It’s been an exciting 10 years of research with AC Immune.
In 2016 Genentech started a Phase III clinical trial for a molecule that targets amyloid-beta in people with prodromal-to-mild forms of AD and a Phase I clinical trial for a molecule that targets tau in people with mild to moderate AD and healthy volunteers.
We’re committed to helping people with severe neurological disorders like AD. By collaborating on antibody approaches that target amyloid-beta and tau, we’re implementing a comprehensive strategy to make it possible.
Tau is found mostly in neurons and seems to function as a component of the cytoskeleton, the scaffold inside of cells that helps provide structure and serves as a roadway for shuttling proteins from one area of the cell to another. But in AD, changes in tau proteins cause them to aggregate in abnormal tangles that are toxic to neurons.
But the problem doesn’t stop there, because toxic tau doesn’t stay inside of cells. “There is compelling evidence that toxic species of tau can actually spread from neuron to neuron through the extracellular brain environment,” said Geoff Kerchner, neurologist and Medical Director at Genentech. “We think this is how tau-mediated toxicity and pathology spread from one brain region into another.”
Intriguingly, the pattern of tau’s spread through the brain seems to be directly related to the symptoms of AD. As tau tangles reach brain regions associated with specific cognitive abilities – such as planning, attention, memory, or language – corresponding symptoms appear.
In fact, the spread of tau occurs years later than the accumulation of Aβ, and its timing appears to be more closely tied to the onset and progression of symptoms – underscoring the importance of pursuing tau-targeting therapies.
Thanks to new imaging techniques, like Genentech’s development of a novel tau tracer known as GTP1 (Genentech Tau Probe 1), we are able to selectively image neurofibrillary tangles in specific regions of the brain using positron emission tomography (PET). This technology could potentially provide a new biomarker to help predict responses to different treatment approaches.
“Just recently, we initiated a pioneering study in people with Alzheimer’s disease to measure the relationship between changes in cognitive function and the spread of tau pathology over time,” said Robby Weimer, Associate Director of Biomedical Imaging at Genentech. “We’re starting to shed new light on the potential link between tau and cognitive decline.”
We know tau is a promising therapeutic target in AD, but how do we turn that insight into action? One possible way to stop tau from wreaking havoc across the brain is to catch it while it’s spreading. In other words, intercept tau in the extracellular space as it’s travelling between neurons. This can be accomplished with therapeutic antibodies that specifically bind to tau.
“In some ways, you can think of these antibodies as ‘tau sponges,’” explains Ayalon. “Once they enter the brain they’re able to find and bind to tau that is floating in the extracellular space, and potentially prevent the spread of toxic tangles to nearby neurons.”
Of course when developing therapeutic antibodies, it’s important to not only select the right target, but also the right type of antibody. Antibodies are incredibly complex molecules that can be engineered with scores of variations. One major feature is whether or not the antibody activates the immune system. Sometimes engaging the immune system is beneficial to more effectively attack a target (e.g., a cancer cell), while in other cases a more “passive” binding role is desired.
Previously, it wasn’t known which approach was better for targeting tau. But new research from Genentech and AC Immune scientists has demonstrated that immune system activation may not be necessary to stop tau. A so-called “effectorless” antibody was sufficient to slow the spread of tau tangles, and also indicated that full-effector tau antibodies may induce indirect toxicity in preclinical experiments.
We are taking a comprehensive approach to understanding a number of neurological disorders, and these new insights into antibodies that target tau underscore our long-standing commitment to basic research in neuroscience. Tau and Aβ are two complementary parts of the Alzheimer’s story, and while there is still much to learn, studying tau could unlock new insights and new treatment approaches for this life-shattering disease.
Read more about these important findings in the following paper from Genentech scientists:
Title Image: Positron emission tomography (PET) scans from patients who received Genentech's novel tau tracer known as GTP1 (Genentech Tau Probe 1). The green/yellow/red colored areas correspond to brain regions with increasing tau tangle burden as highlighted by the tracer molecule. Image courtesy of Robby Weimer's department.