Simple molecule shows remarkable Alzheimer’s reversal in rats

The compounds, developed with support from FAPESP, are easy to produce and are thought to work by breaking down beta-amyloid plaques that build up in the brains of people with Alzheimer's disease. These plaques form when amyloid peptide fragments accumulate between neurons, triggering inflammation and interfering with communication between brain cells.

Targeting Copper to Break Down Beta-Amyloid Plaques

A study published in ACS Chemical Neuroscience reports that the compounds function as copper chelators. By binding to excess copper found within beta-amyloid plaques, the molecules help degrade these toxic structures and lessen symptoms associated with the disease. Tests in rats showed that the compound reduced memory impairments, improved spatial awareness, and enhanced learning ability. Biochemical analysis also revealed a reversal in the pattern of beta-amyloid plaques.

"About a decade ago, international studies began to point to the influence of copper ions as an aggregator of beta-amyloid plaques. It was discovered that genetic mutations and changes in enzymes that act in the transport of copper in cells could lead to the accumulation of the element in the brain, favoring the aggregation of these plaques. Thus, the regulation of copper homeostasis [balance] has become one of the focuses for the treatment of Alzheimer's," explains Giselle Cerchiaro, a professor at the Center for Natural and Human Sciences at UFABC who coordinated the study.

Designing Molecules That Reach the Brain

Using this understanding, the research team created molecules that can cross the blood-brain barrier and remove copper from beta-amyloid plaques. Ten candidate molecules were developed, and three advanced to testing in rats with induced Alzheimer's disease. One compound showed particularly strong results for both effectiveness and safety.

This work formed the basis of the doctoral thesis of FAPESP scholarship recipient Mariana L. M. Camargo, the master's thesis of Giovana Bertazzo, and the undergraduate research project of Augusto Farias. A team led by Kleber Thiago de Oliveira at the Federal University of São Carlos (UFSCar) contributed by synthesizing one of the compounds included in the study.

Improvements in Brain Health and Behavior

In experiments with rats, the compound lowered neuroinflammation and oxidative stress and restored copper balance in the hippocampus, the brain region responsible for memory processing. Treated animals also demonstrated better performance in tasks requiring spatial navigation.

Beyond these behavioral improvements, the compound proved non-toxic in both hippocampal cell cultures and the animals themselves, whose vital signs were closely followed throughout the experiments. Computer models confirmed that the compound can cross the blood-brain barrier and reach the areas most affected by Alzheimer's-related damage.

A Potentially Affordable New Direction for Alzheimer's Care

Alzheimer's disease is a complex and multifaceted neurodegenerative condition with no cure and no clearly defined cause. While an estimated 50 million people worldwide are affected, current treatment options are limited and often provide only partial symptom relief or rely on costly therapies such as monoclonal antibodies.

The findings from UFABC have already resulted in a patent application, and the team hopes to secure industry partnerships to begin clinical trials in humans. "It's an extremely simple, safe, and effective molecule. The compound we've developed is much less expensive than available drugs. Therefore, even if it only works for part of the population, since Alzheimer's disease has multiple causes, it'd represent a huge advance over current options," Cerchiaro celebrates.