Expert: Tau Oligomers Are a Culprit in the Spread of Alzheimer Disease Pathology

During the 2024 Alzheimer Association International Conference (AAIC), Pharmacy Times interviewed Tara Spires-Jones, DPhil, FMedSci, president of the British Neuroscience Association, professor, UK Dementia Research Institute at University of Edinburgh, on synaptic oligomeric tau in Alzheimer disease (AD). She discusses the discovery of tau oligomers as one of the causes of AD pathology spreading through the brain. Additionally, Spires-Jones is hopeful that advancing the understanding of its mechanisms and stopping tau progression through the brain can potentially stop the disease from developing further.

Pharmacy Times: Can you introduce yourself?

Tara Spires-Jones: Hi, I'm Professor Tara Spires-Jones. I'm the current president of the British Neuroscience Association and a professor in the UK Dementia Research Institute at the University of Edinburgh.

Pharmacy Times: What is synaptic oligomeric tau, and what is its significance in the context of AD? How might it differ compared to other forms of tau?

Spires-Jones: So, tau is a protein in the brain that's usually in neurons—which are the cells that do the “talking” in the brain—and it's usually in a monomeric form, which means just 1 copy, and it sort of sits along the microtubules keeping the cell healthy. But in disease states, it gets phosphorylated and then tau falls off the microtubules and sticks to itself. And that's what oligomers [are], it's just a few copies of tau molecules sticking to each other. And these oligomers then are associated with pathology, and then tau goes on to have other things like massive, big neurofibrillary tangles, which are part of the definition of Alzheimer disease (AD).

But what we found in the study I'm presenting here at AAIC, is that these tau oligomers are one of the culprits in the spread of pathology through the brain. So, in AD, pathology starts in the medial temporal lobe, in very small parts of the brain, and as disease progresses, this pathology jumps from brain region to brain region. But we didn't really understand how this happens for many years. There's been some good evidence in mice and in cell systems, but ours is some of the first evidence from human postmortem brain that one of the ways tau might be progressing through the brain is by jumping out of 1 neuron to the next neuron through the synaptic connections. And we saw those oligomers of tau jumping, or at least evidence that they might be jumping, from pre- to post-synapses in human brain.

Pharmacy Times: How does the spread of tau pathology correlate with the progression of symptoms related to AD?

Spires-Jones: The spread of tau pathology through the brain is one of the closest correlates of cognitive decline or symptom progression in AD. So, another even closer correlate is the loss of those synaptic connections. So, not only have we found one of the ways that tau pathology might be jumping through the brain—which is very strongly correlated with symptoms—but we might also be seeing how those synapses are dying and one of the reasons we might be actually losing the functional connections in the brain.

Pharmacy Times: What are some key findings in recent research on synaptic oligomeric tau, and how do these findings advance our current understandings of tau pathology and its impact on AD progression?

So we're actually—I'm really honored—winning a prize for the study that I'm presenting here, which was the Inge Grundke-Iqbal Award for the most influential research in AD past 2 years. And that study—which we published last year—is where we found this key finding that oligomeric tau clumps inside individual synapses in human brain and we found some indirect evidence that it might be progressing through the brain by jumping through synaptic connections. So, that's sort of the main finding.

But I'm going to go beyond what we've already published and present some new data in progressive supranuclear palsy (PSP), which is another tauopathy, another debilitating neurodegenerative disease, where we had a similar finding that oligomeric tau could be jumping through the brain through synaptic connections. And beyond that, with my colleague Claire Durrant in Edinburgh, were able to look in living human brain slices from surgical resected tissue, and when we challenged live human brain with tau from PSP brain, we could see [that] living human synapses can take up that pathological tau. So, we’re very excited to share new results as well.

Pharmacy Times: Could the mechanisms involving synaptic oligomeric tau be relevant to other neurodegenerative diseases beyond AD?

Spires-Jones: So yeah, we've just talked about AD, we've got evidence that we'll present from both AD and PSP that these oligomers might be jumping through the brain, and I'm really hopeful that if we could stop the progression of tau pathology through the brain, we could really stop disease in its tracks. We could stop the disease progression. So, in the future, we're excited to work with companies and people around the world working on ways of stopping this progression. If we can really understand how is this tau getting out of 1 cell into the next cell, we have a chance of stopping it.

Pharmacy Times: How do you envision the future of research in this the space, specifically surrounding tau? What are the next steps?

Spires-Jones: In the short-term, we'd really like to understand how this oligomeric tau is getting out of 1 side of the synapse and into the other, so, we're doing active research, looking for binding partners, and looking for mechanisms both in the neurons and in the glial cells that connect them.

In the long-term, of course, our vision is like all of us at this conference, we want a world without dementias, and in the long-term, I really am hopeful that if we can understand these mechanisms and stop this tau progression through the brain, we could stop the disease in its tracks. And maybe, the brain could even recover a little bit, so maybe people have a chance of getting a bit better.