Can the brain really heal itself?

For the first time in the history of Alzheimer’s treatment, drugs can now eliminate the plaques that cause some of the disease’s most challenging symptoms, including memory loss and confusion. This means that instead of just treating or masking these symptoms, doctors can address the underlying cause.

But this breakthrough has also revealed something unexpected: For many Alzheimer’s patients, eliminating the plaques wasn’t enough to fully reverse memory loss. 

“We have FDA-approved antibodies that can clear out the plaques completely, and we are finding out that’s not the whole story,” said Varghese John, PhD, director of the Drug Discovery Laboratory at the Mary S. Easton Center for Alzheimer’s Disease Research and Care at UCLA. “Once you clear the plaques, we need drugs to turn the neurons back on. We also need drugs that can be administered early on to provide protection.”

UCLA Health researchers are searching for treatments that don’t stop at clearing the damage Alzheimer’s leaves behind, but also actively help the brain heal.

Harnessing the brain’s own defenses

Finding drugs that can help the brain repair itself began in an unexpected place: the biology that already protects a healthy brain.

“I believe that the human body is always trying to repair itself,” said Jessica Rexach, MD, PhD, an assistant professor of neurology at the David Geffen School of Medicine at UCLA. “When that’s not successful, it’s because something is getting in the way of that ability. Those are the repair systems we want to restore.”

Even in a brain affected by Alzheimer’s, some cells hold up better than others, resisting the damage that overwhelms the cells around them. Certain regions of the brain fare better, too. Dr. Rexach has built her research around understanding what makes those cells and regions resilient, and whether that natural protection can be activated in the cells that are failing.

“We can find out their ‘secret sauce’ and try to reactivate it,” Dr. Rexach said.

Her lab analyzes large datasets of human brain tissue, comparing the cells that hold up to those that don’t and searching for the biological signals that make the difference. Those signals become the targets for a new kind of drug that works by strengthening the brain’s own capacity to protect and repair itself.

Because these targets come from the body’s own biology, drugs based on them may be better tolerated by patients, which could shorten the time it takes to get the medications out into the world.

Once Dr. Rexach’s team identifies a promising target, it moves to Dr. John’s lab, where medicinal chemists search hundreds of thousands of compounds, including existing FDA-approved medications, for ones that can activate the same protection in vulnerable cells.

“Finding the targets is the critical step in the drug discovery process,” Dr. John said. “Then we need to find the right compound to modulate that target.”

Turning insights into treatments

The strategy is already producing promising results. Dr. Rexach’s team has identified the brain’s natural repair systems that break down in Alzheimer’s, uncovering multiple new targets for restoring them. 

One promising line of work focuses on the brain’s immune cells, which normally clear away toxic debris but become overwhelmed as the disease progresses. Dr. Rexach’s lab has found conditions in which these cells stay resilient, continuing to protect neurons even under severe stress, and is now working to reproduce them with targeted therapies.

Dr. John’s team, meanwhile, has developed a molecule that travels to the brain and helps prevent the buildup of damaging plaques before they form. In animal studies, it improved both learning and memory. 

The lab has also created molecules that restore healthy brain activity linked to memory, with early results showing recovered cognition in animals that had already declined. One of these molecules has been licensed to a biotechnology company for further development, a meaningful step toward reaching patients.

“You could imagine a scenario where if a person has an Alzheimer’s risk gene, they could take a drug like this early on to start building neuronal protection,” Dr. John said. 

One breakthrough, many diseases

The ambition behind this work, however, reaches beyond any single drug or disease. Because many brain diseases share the same broken repair systems, a discovery in Alzheimer’s could open new possibilities for patients facing Parkinson’s, other dementias, and conditions not yet fully understood.

“We’re not just thinking about bringing one drug through, but many,” Dr. Rexach said. “Our screens are designed to test hundreds of different targets simultaneously. This is one of the reasons that it's a really, really important time for translational neuroscience. We have to get this right, and I think once we do, it’s going to be a completely different world.”