Loss of brain protein eases Alzheimer’s symptoms and brain damage in mice

Scientists from Max Planck Florida Institute for Neuroscience in collaboration with Florida Atlantic University and East Carolin University have discovered that genetically eliminating Centaurin-α1, a specific brain protein previously associated with Alzheimer’s disease progression, can lessen many of the cognitive deficits and brain damage caused by the disease in mice.

In brief:

• Centaurin-α1 contributes to Alzheimer’s damage: Eliminating Centaurin-α1 reduced neuroinflammation, amyloid plaque buildup, and synaptic loss in a widely used mouse model of Alzheimer’s disease.
• Improved learning and memory performance: Alzheimer’s disease model mice lacking Centaurin-α1 showed improved spatial learning, suggesting cognitive symptom improvement.
• A potential new therapeutic target: Centaurin-α1 may contribute to several Alzheimer’s-related deficits, making it a promising direction for future treatments.

New research published in the journal eNeuro examined whether eliminating a protein that is elevated in the brains of those with Alzheimer’s could prevent or reduce damage and behavioral symptoms in a mouse model of Alzheimer’s disease.

“Previous work from our research team and others found evidence that a specific protein named Centaurin-α1 is involved in the progression of Alzheimer’s damage within neurons,” explained lead author of the study, Dr. Erzsebet Szatmari. “To confirm the role of this protein and see if it might be a good therapeutic target, we tested whether genetically removing it would prevent or slow disease progression in a mouse model of the disease.”

The scientists used a well-characterized model of Alzheimer’s disease in mice. The disease model (called J20) contains two genetic mutations associated with rare familial variants of Alzheimer’s disease. These animals develop changes in brain tissue and behavioral deficits characteristic of many symptoms seen in human Alzheimer’s disease, including neuroinflammation, accumulation of neuronal plaques, synapse loss, and impairments in spatial memory and learning.

Removal of Centaurin-α1 lessens disease damage

The research team genetically removed the Centaurin-α1 protein from the Alzheimer’s model mice to investigate whether this would alter the development of disease symptoms. Some of the earliest deficits seen in the disease model include neuroinflammation. While the Alzheimer’s model mice showed widespread markers of neuroinflammation, those lacking Centaurin-α1 did not.

The removal of Centaurin-α1 also reduced amyloid plaque formation, a hallmark of Alzheimer’s disease. In the hippocampus, a brain area highly affected, plaques were reduced by about 40%. However, this reduction was not observed in the neocortex, suggesting that plaque formation in the disease may differ across brain regions and that treatments to prevent its buildup may need to be multipronged.

Along with improvements in neuroinflammation and plaque buildup, the researchers found that removing Centaurin-α1 partially protected against the loss of neural connections in the hippocampus, critical for spatial learning. This finding suggested that impaired spatial learning characteristics seen in the disease model may also be improved by removing Centaurin-α1.  Indeed, removal of Centaurin-α1 improved spatial learning deficits in mice.

Centaurin-α1 as a potential therapeutic target

“We were encouraged by the behavioral changes seen in the Alzheimer’s model mice that lacked Centaurin-α1, confirming that the protein contributes to the progression of cognitive symptoms and therefore might be a valuable therapeutic target. However, we still have much to learn about how it is working in the brain to worsen the disease,” said Szatmari.

To begin to understand how Centaurin-α1 might influence disease progression, the research team compared the brain composition of healthy mice, disease model mice, and disease model mice without Centaurin-α1 using gene expression analysis. As expected, many components in the brain tissue from the disease model mice were altered, with some components increasing and others decreasing. However, the disease model mice lacking Centaurin-α1 showed a somewhat normalized brain composition, with components that had increased reducing, and those that had been reduced, increasing.

“We think that Centaurin-α1, may play a multifunctional role in regulating signaling processes in the brain that alter gene expression and the composition of many molecules. This aberrant signaling may enhance disease progression and symptoms through metabolic deficits, neuroinflammation, amyloid processing, and dysfunction of neural connections,” describes senior author and MPFI scientific director Dr. Ryohei Yasuda. “Although more research is needed to determine whether reducing Centaurin-α1 can benefit the human brain, evidence so far suggests that Centaurin-α1 is a promising candidate for future therapeutic development.”

The team is moving forward in investigating Centaurin-α1 as a powerful regulator of multiple Alzheimer’s-related processes and whether reducing its activity in adulthood, rather than deleting it from birth, could also slow disease progression. Recently, they found that loss of Centaurin-α1 reduced symptoms in a mouse model of another disease, multiple sclerosis (MS), suggesting that its role in disease progression may extend to multiple neurodegenerative diseases.

Szatmari, E. M., Moran, C., Cohen, S. J., Bashtovyy, D., Jacob, A., Bunner, W., Phipps, M., Lora, J. C., Stackman, R. W., & Yasuda, R. (2025). Lack of ADAP1/Centaurin-α1 Ameliorates Cognitive Impairment and Neuropathological Hallmarks in a Mouse Model of Alzheimer’s Disease. eNeuro. https://doi.org/10.1523/ENEURO.0063-25.2025

This work was funded by the BrightFocus Foundation, Community Foundation of 54 the Palm Beaches, NIA, Max Planck Foundation, ECU Startup funds, and ECU URCA awards.  This content is solely the authors’ responsibility and does not necessarily represent the official views of the funders.