May 09, 2022
Forgetting how to brush your teeth. Losing your car keys inside the refrigerator. Giving a blank look of unrecognition when your spouse of 50 years brings flowers to your hospital room.
Alzheimer’s disease manifests itself in these heartbreaking ways and many others, the result of the brain becoming riddled with abnormal proteins. Their names are well-known by now after decades of research – beta-amyloid, which forms clusters of protein fragments called plaques around brain cells, and tau, which forms twisted tangles within the brain cells themselves.
To date, Alzheimer’s researchers have predominately focused on ways to reduce the accumulation of beta-amyloid plaques and tau tangles in the brain. But these efforts have had limited success. Plus, the bulk of Alzheimer’s research has tended to focus on very rare forms of the disease, cases that can be linked to a single gene mutation, partially because they’ve been easier to study. However, that’s not the reality for most people diagnosed with Alzheimer’s. Most cases have no one clear cause, instead they likely result from a complex interaction of many genes, the environment and normal aging.
Understanding Alzheimer’s remains the scientific challenge of our generation. Seeing a challenge and unmet need, Alzheimer’s researchers supported by Harrington Discovery Institute at University Hospitals are attacking the disease in novel ways, with some early successes already on the board.
Novel therapeutic approaches under way at Harrington Discovery Institute at University Hospitals
Harrington Scholar Stephen Strittmatter, MD, PhD, for example,at Yale University is working to understand how Alzheimer’s progresses, specifically honing in on how beta-amyloid interacts with two other proteins in the brain -- PrP-C and mGluR5. PrP-C is short for cellular prion protein, a small molecule on the surface of the cell that contains both a carbohydrate and a protein, most known for its role in causing prion diseases such as bovine spongiform encephalopathy (BSE or "mad cow" disease) in cattle and Creutzfeldt-Jakob disease (CJD) and variant CJD in humans. Type 5 metabotropic glutamate receptor (mGluR5) helps with the signaling of glutamate in the brain – the main neurotransmitter that excites neurons, helps formal neural networks and affects the changes that occurs at synapses, the junctions between neurons that allow them to communicate.
“Our attitude is that what really matters is identifying which proteins beta-amyloid interacts with on the surface of the neurons, because dysfunctional neurons are what cause people to lose learning, memory and cognitive function,” he says. “We want to understand how neurons respond to these toxic aggregates. That opens the door to a different kind of treatment, which is blocking those pathways that are present in the neurons and at the synapses that mediate this damage. We don’t have to try to clear out all the plaque and tangles out of the brain. We can simply use a drug that protects the neuron from the presence of the plaques and tangles.”
He and his colleagues have discovered agents that can block PrP-C and mGluR5 from binding with beta-amyloid. They don’t “clear out” the “piled up” beta-amyloid, as he calls it, but rather act as a type of chemical force field protecting the synapses conveying signals between neurons, allowing the brain to function normally. Not wanting to put all their eggs in one scientific basket, the team has identified three distinct blocking agents – a large molecule, a small molecule and an antibody, which work in different ways.
“Having three shots on goal seems like a stronger proposition than a single shot,” Dr. Strittmatter says.
So far, all three approaches are working as intended. In mice designed to approximate a person with early to moderate Alzheimer’s disease, a month or more of treatment with each agent has led to some stunning results. The density of synapses in the mice brains recovered to normal, even though there was still amyloid in the brain, and the animals’ performance on memory tests improved.
The small molecule targeting mGluR5 behind these impressive results is now being tested for safety in humans in a Phase 1 clinical trial. Dr. Strittmatter says he expects the large molecule and antibody targeting PrP-C to follow a similar path soon.
“With the PrP-C approaches, their efficacy in pre-clinical models is as strong as the mGluR5 drug that’s already in trials,” he says.
Targeting neurotransmitters for optimal activation
Harrington Scholar Jerri Rook, PhD, from Vanderbilt University also has an Alzheimer’s small molecule drug candidate in Phase 1 clinical trials. Dubbed VU319, it selectively increases the activity of a specific target of acetylcholine in the brain called M1. Acetylcholine is a neurotransmitter that is significantly diminished in the brains of people with Alzheimer’s disease. M1 is short for muscarinic acetylcholine receptor subtype 1; it plays a crucial role in learning and memory.
Previous Alzheimer’s compounds targeting M1 were akin to using a massive hammer to swat a fly, Dr. Rook says – over-activating the system and causing unwanted side effects. She and her team knew they had to find a drug candidate that would provide more of a fine-tuning approach, selectively enhancing naturally occurring acetylcholine only when needed. It took a herculean effort to screen more than 160,000 compounds, but they found one that fit the bill.
“We only want M1 to be activated in a normal setting, when acetylcholine is supposed to be there and is supposed to be working,” she explains. “That’s what our compounds do. They have no activity by themselves. They only increase the activity of the endogenous, normal physiological acetylcholine. So we’re able to boost it with a fine-tuning mechanism, rather than hitting it like a hammer. We turn it up in the correct time frame when it needs to be activated.”
Dr. Rook and her team have tested VU319 in normal, healthy rodents, rodents designed to model Alzheimer’s disease with prominent beta-amyloid and tau, as well as aged rodents to approximate human aging. All three groups have shown increases in learning and memory. Importantly, data from Phase 1 clinical trials have shown no safety concerns.
“Those data were all very positive,” she says.
VU319 has been licensed to Acadia Pharmaceuticals for further development. Already, Dr. Rook is on the lookout for a back-up compound should troubles arise with the candidate drug, even though results to date have been very encouraging.
“You want to have a back-up,” she says. “It’s an important part of drug discovery.”
Linking traumatic brain injury (TBI) and Alzheimer’s disease through blood-tests
As Director of the Center for Brain Health Medicines at Harrington Discovery Institute, Andrew A. Pieper, MD, PhD, is also actively engaged in his own promising Alzheimer’s research. The Harrington Investigator and his team are keenly interested in the link between traumatic brain injury (TBI) and Alzheimer’s disease. TBI is the third-leading cause of Alzheimer’s disease, but so far the reason for this association has been unknown.
However, new results from Dr. Pieper’s lab represent a significant step in solving the mystery. Experiments with mouse models of TBI show higher levels of acetylated tau protein – the same acetylated tau protein found in people with late-stage Alzheimer’s disease. Acetylation occurs when an acetyl group takes the place of a hydrogen atom in an organic compound. Dr. Pieper’s laboratory has now shown that acetylation of the tau protein causes collapse of the long axons of neurons that send electrical impulses from one to another.
Acetylated tau was also not limited to the brain – in animal studies it spilled out of the brain and showed up in the blood as well, raising the possibility that a blood test for the substance could be part of monitoring brain health after a TBI or other brain injury. His group also found elevated levels of acetylated tau in blood tests of people who’ve suffered a TBI.
Can this harmful process be halted? Or even reversed? It appears it could be. Dr. Pieper and his colleagues have discovered a molecule called P7C3 that boosts an important substance that brain cells need for energy. That, in turn, triggers a beneficial chain reaction, with a stimulated enzyme doing “clean up” duty, removing the offending acetyl groups from tau.
“When we gave animals P7C3 after injury, we were able to remove the acetyl groups that were otherwise being added, and that protected the animals from cognitive decline,” Pieper says.
Dr. Pieper and his team have also identified two specific non-steroidal anti-inflammatory drugs (NSAIDs) – think aspirin or ibuprofen – that can block tau acetylation in the first place. Salsalate and diflunisal both quickly inhibited acetylation of the tau protein and completely blocked nerve cell degeneration, protecting the mice from TBI-related brain decline. Importantly, the group’s research with 7 million patient records also shows that people who use these medicines have a significantly lower occurrence of Alzheimer’s disease than those who had just taken aspirin.
“The difference is that these drugs inhibit tau acetylation, and aspirin doesn’t,” he says. “We’re hopeful that these are medicines that could be repurposed right now for patients and might be protective.”
Improving blood flow to the brain may improve memory
Harrington Discovery Institute President Jonathan Stamler, MD, is addressing the unmet need in Alzheimer’s disease from an entirely different vantage point – with a focus on the tiny microvessels in the brain that supply blood to keep vital tissue nourished.
“There is a school of thought that blood flow in small blood vessels that supply oxygen to tissues is a critical factor in the development of Alzheimer’s disease,” he says. “Impairment of that blood flow is a very early and causal event in Alzheimer’s disease.”
Poor blood flow in the brain is a known cause of what’s called vascular dementia. But Dr. Stamler says this process also has a connection to what goes on in the Alzheimer’s brain. And importantly, he and his team have discovered a way that may stop it from happening.
Building on his discovery that a source of nitric oxide from the red blood cells inside these vessels actually keeps them open, he and his team have developed tools to both measure and improve blood flow inside the human brain.
“We’re working on how to improve blood flow in those small blood vessels so that memory is improved and risk of Alzheimer’s is diminished,” Stamler says.
Progress is occurring right now.
“We’re working in people and we have ways to measure very clearly the nitric oxide coming out of their blood cells that keeps those blood vessels open, and we’re able to manipulate those levels in people to improve blood flow. We are hopeful that this will represent an important new approach to improving memory and protecting against Alzheimer’s disease.”
With all these research efforts supported by the Harrington Discovery Institute, the goal is the same: To leverage scientific discovery into real-world therapies for Alzheimer’s patients. In months and years, not decades.
“We’ve made so much progress,” Dr. Stamler says. “There’s no reason to believe that we can’t protect the brain the way we protect any other organ in the body. We just have to figure out how to do it. And at Harrington Discovery Institute, we are doing just that.”
Given the ongoing toll of Alzheimer’s, there’s no time to waste.
2020 Harrington Scholar-Innovator
University Hospitals - Cleveland
2018 Harrington Investigators
University Hospitals - Cleveland
2012 Harrington Investigators