While the heavy presence of the protein amyloid in the brain has been a cornerstone of Alzheimer’s research, Dr. Li Gan and her team are focusing on a different protein called tau, and the key it holds in cognitive decline.
Their work centers on a rare mutation, Christchurch, which appears to reduce inflammatory responses in the brain, including decreasing tau’s uptake into neurons, and supporting microglia cells to clear tau more effectively. It’s a direction Dr. Gan believes shows great promise in the fight against dementia and Alzheimer’s disease, she says.
“The take-home message is not amyloid, but tau and inflammation as the drivers of a cognitive decline,” says Gan, Director of the Helen and Robert Appel Alzheimer’s Disease Research Institute at Weill Cornell Medicine. “We have to be able to target that beyond amyloid therapy.”
You can hear more from Dr. Gan and her team’s important research in her talk during the DOC 2025 session, “Neurodegenerative Diseases: State of the Science and What You Can Do Now, in our video, or read our lightly edited transcript below.
TRANSCRIPT:
Dr. Li Gan
Thanks very much. It is really a pleasure to be here. In the past, a day and a half, I’ve been deeply inspired by the talks and also the conversations. So today I will talk about how to enhance resilience. I wanted to start with a very uplifting story, of Donna Algeria. So she lived in a small village in Colombia along with her extended, relatives.
They carry a very aggressive, early onset Alzheimer’s, mutation. So many of her relatives, develop, severe dementia in their 40s. But Donna, Algeria has no symptom until, even late into the 70s. So what is, happening in the rain? So this, when we looked at, her brain using imaging. And the field is astonished. How do I do? How come the. It’s not showing up? So, when. Oops. So we just have to, imagine it. So I don’t know why it’s not showing up. In my advance. It, So the field was really astounded, when we looked into their brain so consistent ways, this mutation, which lead to increased amyloid plaque deposition.
Donna Maria, Donna Algeria, as a brain is full of amyloid, it’s actually more amyloid than her symptomatic relatives. But her brain is really, lacking another pathological hallmark, which is tau tangles. So what is tall? Tau is, the protein that aggregates in the neurons and can spread, damaging neuronal function, but also spread from one neuron to another and lead to cognitive decline. And this is the reason. Donna Olivia is free of, the symptom.
This relationship between amyloid and tal is, replicated also in the general Alzheimer population. So if you look at this slide, you would appreciate that the culprit of memory loss is tau, not amyloid. So this is a Pet scan, patients that, looking at their amyloid deposition as well at healthy position and along with a cognitive decline.
You can see from the, light blue, if the patient only positive to amyloid plaques, they have very, very little decline over the six period of time. But if the, patients had also positive for the healthy position, as you can see for those other two, a darker, the darker, traces that they had much more severe decline of cognition.
This tells us that it is very important to, to, stop the Tau toxicity. So this also can explain why the current anti amyloid therapy is not able to stop memory loss. Even though it was, even the patients are treated at very early stage. So, my lab in the past 50 years has been trying to understand how to enhance resilience and resistance against all.
As Eric mentioned, that my lab has develop strategies to enhance Tau clearance using both small molecule cures as well as monoclonal antibodies. But what I will tell you today is about our work in, understanding how the resilience appeal carried by Donna and Olivia that can help us develop more effective drugs. So it turns out some are really carry a mutation that is very rare.
We call it the Christchurch mutation. The April year Leo and this rare nature’s gift, I call it, shielded her from her brain from the tau buildup and memory loss. So how to study it? We wanted to study the mechanism so we can turn this nature’s gift into a small molecule. Appeals. So we used, CRISPR screen, or CRISPR editing, as Claire mentioned, in her talk to recreate the Christchurch mutation, both in the animal model mouse models as well as, IPSC, derived stem cells.
We then turned the stem cells into, immune cells, which are microglia, and then look at the molecular signatures that is generated or altered by this, resilience early. So this is a cartoon. And the, the paper is published, and showing that, how this Christchurch alter the response of immune cells to tau.
In the absence of the Christchurch mutation, you can see that the cells respond to that healthy position with, inflammatory. It was a very strong, in fact an inflammatory response at including antiviral response, in particular the interferon response. But if you have this Christchurch resonance mutation, then the cells have a much more subdued, response to these tau proteins and that reduce the immune stress.
How did this happen? So, the research allows us by going into deep into the immune cells. And we discovered that the key protein that drives this difference is a protein called cGAS. And you heard it from the Q and A yesterday. cGAS is a very ancient alarm system.So it senses a double strand DNA in the cytosol where it shouldn’t be.
As a response triggers antiviral, response because the cells established in DNA in the cytosol as virus. So then it started to launch this antiviral response using that and, interferon response. But the double strand DNA could also come from nucleus, as shown in this slide, especially in the form of, chromatin fragments. When the genomic T genome becomes unstable. You have a jumpy DNA. It could also come from mitochondria, which is where we found what tau protein triggers. We found that when immune cells of exposed to tau aggregates that the micro mitochondria become damaged, it becomes leaky. So the mitochondrial DNA, which orange from bacteria now leak into the cytosol, triggers suggesting activation. So the interferon response will become rampant even though there is no infection.
This is how our brain is damaged. In response to these, to the hyper active alarm system. So how do we turn this, discovery into a therapy? So because we now cGAS is a core of the problem, we developed, small molecule inhibitors at this brain penetrant and then use it to treat the mouse model mouse that carry, having the Tau build up what we found is astonishing.
We found that the cGAS inhibitor can actually mimic the Christchurch mutation effects in the form of molecule signatures in the form of dampened inflammatory response, as well as in the form of reduced tau spread. So, you heard probably from the QnA yesterday, were very also excited about the link of cGAS with this exceptional longevity of naked mole rats.
Naked mole rats, as you probably heard from yesterday, live ten times longer than their rodent relatives. So the mutations or the differences of the naked mole rat cGAS is a four amino acid that lead to dampened interferon response to the W 28, but promoted the DNA repair mechanism. So we’re already, excited about this discovery and hoping we can harness this difference of naked mole rat cGAS and a small molecules to actually mimic, this, in the new function of cGAS.
Take home message not amyloid, but tau and inflammation as a drivers of a cognitive decline. And we have to be able to target that beyond amyloid therapy. And one of the ways to do it, we heard today or we heard from that today, which I was very inspired, is to strengthen our mitochondria and reduce our stress.
We also are seeking for partnership to further develop this first in class, brain permeable, cGAS inhibitors so we can actually stop tau from build up and build the resilience. Thank you.