Paths to treatment and hope for Alzheimer's patients

During a recent JAXtaposition event, Associate Professor  Kristen O'Connell, Ph.D.Kristen O’Connell’s research program is focused on understanding the impact of diet, body weight and peripheral hormone signaling on neuronal excitability and plasticity in the hypothalamus and other brain regions associated with the regulation of food intake and body weight.Kristen O’Connell, Ph.D., and Vice President for Translational Science and Network Alliances discussed the unique challenges of Alzheimer’s disease (AD), a novel protein that holds potential for therapeutics, and the next steps in drug discovery for AD.

O’Connell examines the interaction between genes and environment, such as diet and obesity, on resilience and susceptibility to AD using genetically diverse mouse populations. She is also involved in collaborative efforts to create new models of AD and related dementias that better capture the complexity of this disease.  

“There's a great need for new models, new targets and new treatments,” said Bormann. “I'm proud to say that The Jackson Laboratory is very strongly part of this fight.”

An urgent need for preclinical models

 The O'Connell LabThe overarching goal of my NIH-funded research program is to understand the neural control of appetite and how diet and body weight affect the excitability of the neurons in key CNS circuits responsible for food intake.The O’Connell lab , in collaboration with others at JAX including , is focused on creating a new, more translatable preclinical mouse model to better understand the earliest molecular and cellular changes associated with AD and identify factors that can protect against the development and progression of disease and mitigate symptom severity.

O’Connell said the need for better preclinical models is urgent: “By the time most people present to their physician, noticing memory loss and cognitive impairment, the reality is that the underlying pathology associated with the disease is already in progress and in some cases has been for decades. So by the time you go to the doctor, the disease has already set in.”

O’Connell and collaborators developed a new genetically diverse panel of mice to study three major risk factors for AD: age, genetic background and environment. They generated two distinct populations of mice - one carrying a gene that makes them highly susceptible to AD, and one that does not carry this gene. “So we have mice that are resilient and mice that are highly susceptible, and then almost everything in between,” she said. 

By studying how these mice performed on a long-term memory task and then examining the  protein levels in their hippocampus (a part of the brain that is critical for the formation of new memories, and one of the earliest areas of pathology in the development of AD in both animals and humans), the team was able to identify a unique biological target for AD – a gene called TrpC3.

A unique biological target

TrpC3 “had not previously been associated with memory, so this was actually a really exciting finding,” said O’Connell.

When the researchers looked across the genetically diverse panel of mice, they saw an inverse relationship between the expression levels of TrpC3 in the hippocampus and performance on a spatial memory task. “So the ability to hold something short-term in memory such that there were high levels of TrpC3 expression were associated with poor memory,” said O’Connell.

By decreasing the function of TrpC3, O’Connell and her colleagues found that in young mice, memory improved on a long-term memory test. In aging mice, decreased function of TrpC3 prevented cognitive decline such that their performance on both a working memory task and a long-term memory task was nearly the same as in their young counterparts. And in mice who were exhibiting cognitive impairment, “we could actually rescue their cognitive impairment” by reducing TrpC3, said O’Connell. “At 10 months of age, they were performing as well as their wild-type counterparts that did not have the same susceptibility to AD.” Lastly, by knocking down TrpC3, researchers found that the formation of amyloid beta plaques (hallmark neuropathologies of AD) were mitigated.

O’Connell noted that it’s important to recognize that we now know that AD is not a single disease. “It's actually a spectrum disorder with differences in the severity of symptoms and the domains in which those symptoms occur, where patients can have not only memory impairment, but also experience metabolic dysfunction,” she said. “They can exhibit sleep loss and sleep dysfunction, changes in anxiety and other neuropsychiatric symptoms. So there are many subtypes of AD, and it's unlikely that a single drug, especially one with a single mode of action will be able to address all of those.” TrpC3, on the other hand, has a unique appeal as a biological target because it appears to have multiple mechanisms of action.

“A single target that has multiple modes of action, both enhancing neuronal excitability and thus cognition, as well as influencing mitigating the development of amyloid-beta plaques in the brain, has much more potential to be a broader therapeutic target for AD and represents a true disease-modifying agent to actually inhibit the progression or stop it altogether,” she said. 

A promising drug discovery program

Bormann, who has nearly 30 years of experience in both pharmaceutical and academic science, as well as leadership in biotech and pharmaceutical business development and licensing, is focused on identifying new business opportunities arising out of the Laboratory’s research and development strategies.

“When I met Kristen and Catherine [Kaczorowski] and I saw the work that they were doing, and I saw that they were able to really prove that TrpC3 could be a powerful biological target, I said, ‘We've got to do at least some initial drug discovery or find a compound of some kind that can alter the activity of TrpC3,’” she said.

Bormann set up a drug discovery team as a virtual biotech company to research TrpC3 further. The team has tens of thousands of pages of data that they share virtually, and has been testing the TrpC3 molecule with thousands of molecules via high throughput screens, looking in specialized libraries for compounds and synthesizing the molecules.

As they design molecules on a computer, they are designing them in silico. “What we can do is actually project what they'd look like in three dimensions and see if they would fit into this model and fit into these pockets,” said Bormann. “So is it too big? Do we have to take away some of the phenyl groups and other chemical entities? Do we have to make it smaller? Do we have to make it more water-soluble? Do we have to make it more fatty soluble? We're able to do a lot just on the computer before we actually synthesize the molecule.”

Over the course of approximately a year and a half, the team synthesized about 200 different reference compounds and well over 300 brand new Jackson Laboratory compounds that antagonize and bind to TrpC3. “So, at this point in time, I'm excited to tell you that we have some very potent inhibitors of TrpC3, and we're down to a small family of maybe 5 to 10 molecules that we think are extremely promising,” said Bormann.

Next, the team will examine the physical properties of these compounds. “We have to know what the half-life is, for example, how long does it stay in your body? We have to know if you're taking this compound orally, does it get into the brain?” she explained.

Ultimately the goal is to take one or two lead compounds that have the most promise and go back to the mouse models to conduct cognitive memory testing. “That will be a very, very exciting day for us,” she said.

“This is really an extraordinary program for us, very high risk, but potentially very high reward,” said Bormann. “If things go well, we look forward to having a molecule that was generated from The Jackson Laboratory go into clinical trials in two to three years.”