Lea Grinberg, MD, PhD, University of California, San Francisco, CA, discusses the diagnostic and therapeutic implications of caspase-cleaved tau in Alzheimer’s disease (AD). Data from various investigations have shown that several tau post-translational modifications may be relevant to AD pathology. Active caspase-6 (aCasp-6) creates a truncated form of tau that is prone to aggregation and toxic to the brain. By using a monoclonal antibody specific to truncated tau (tr-tau), its presence can be measured in neurons. A study using multiplex immunofluorescence to quantify neuronal aCasp-6, tr-tau, and phosphorylated tau (p-tau), showed that many neurons with tr-tau did not show phosphorylated changes, suggesting that different classes of neurons are vulnerable to different pathways and therefore, only targeting p-tau may not be sufficient. Furthermore, these findings indicate that modulation of aCasp-6 to reduce tr-tau pathology is a promising therapeutic strategy for AD. This interview was conducted during the 2022 World Congress on Controversies in Neurology (CONy) meeting.
Transcript (edited for clarity)
That’s very exciting and we have a paper coming out in about two weeks, it just has been accepted. When we are looking for disease in the brain, in the diagnostic setting, or even on the research setting, again, we use antibodies to detect changes caused by this disease. So for instance, in the case of Alzheimer’s disease, we are looking for tau changes and amyloid changes. So for this, we use antibodies...
That’s very exciting and we have a paper coming out in about two weeks, it just has been accepted. When we are looking for disease in the brain, in the diagnostic setting, or even on the research setting, again, we use antibodies to detect changes caused by this disease. So for instance, in the case of Alzheimer’s disease, we are looking for tau changes and amyloid changes. So for this, we use antibodies. So which antibodies do we use? The field came up with certain antibodies that we believe are expressed in every disease, in every step of the disease. It’s almost like a screening. If it’s not detected by these antibodies because it’s not there. And in the case of tau, it’s antibody against phospho-tau. Now, with this study, again, using this technology that we can label different markers at the same time in tissue, we realize that there are other types of tau changes, that at least experimental models are very harmful to the cell, that when they express in the cell, we don’t have phospho-tau in the same cell.
So it means that if we take 100 neurons and we look for tau changes, and, let’s say, that we find that 40 of them will have these phospho-tau changes. So what we’ll do about it, to say, “Okay, these neurons that have the phospho-tau changes, they are the most vulnerable, so these are the ones we are trying to understand the select vulnerability, these are the ones we are trying to understand the secret.” With this study, we detected that another probably 13 neurons of this 100, will have truncated tau, which is very toxic, but they don’t have phospho-tau. So we had never imagined that they were sick, if we were not doing this multiplex analysis. Now, what do we do with this? So several things. So first, there are different class of neurons that seems to be vulnerable to a different pathway.
So just treating for phospho-tau probably won’t do the trick. The second thing that’s even more excited is that this other type of tau, this truncated tau, it’s usually caused by activation of something called caspase-6. So caspase-6 is a molecule that has been associated with cell death, with apoptosis. But more recent studies have been shown that caspase-6, especially in the brain, has other activities. And one of this is to truncate tau. And there are drugs being developed to inhibit caspase-6 activity. So this class of neurons not only are excited to be discovered because we are seeing part of the disease that we didn’t know before, but it seems that there is a therapeutical avenue for dealing with these changes. And then of course, can be a game changer in people with Alzheimer’s disease, in terms of treatment.