How targeting a single protein could shift the fight against one of the world’s most complex neurological diseases
Alzheimer’s disease, a condition marked by memory loss, cognitive decline, and significant brain damage, continues to defy efforts for lasting treatments. In recent years, scientists have identified many culprits behind the progression of Alzheimer’s—but new research suggests that targeting just one protein might have outsized effects. Meet Centaurin-α1 (also known as ADAP1), a protein that could hold the key to slowing, or possibly reversing, some of the most troubling changes in Alzheimer’s disease.
The Role of Centaurin-α1 in Alzheimer’s Progression
Centaurin-α1 is no newcomer to the spotlight—previous studies have shown that it is elevated in the brains of people with Alzheimer’s and appears particularly associated with regions of damage. This protein is deeply involved in the functioning of neurons, regulating how neuronal connections grow and change. Its increased presence in disease states led researchers to suspect it might play a fundamental part in worsening cognitive and behavioral symptoms.
Dr. Erzsebet Szatmari, the study’s lead author, notes, “We found evidence that Centaurin-α1 is involved in the progression of Alzheimer’s damage within neurons, but we needed to know if it was a good therapeutic target.” The only way to know for sure? Try removing the protein and see if the brain fares better.
A Subtraction That Yields Big Gains
The study, published in the journal eNeuro, set out to answer this question using a well-established mouse model of Alzheimer’s disease, known as J20. These mice carry genetic mutations that cause classic Alzheimer’s pathology: amyloid plaques, synaptic (neural connection) loss, inflammation, and memory problems.
Researchers crossbred these Alzheimer’s mice with mice whose Centaurin-α1 gene had been deleted, creating a new group that lacked the protein altogether. The results were striking:
- Reduced Neuroinflammation: Normally, Alzheimer’s mice develop widespread inflammation in the brain. But those missing Centaurin-α1 showed far fewer markers of this damaging response.
- Fewer Amyloid Plaques: In the hippocampus—a region essential for memory and one of the hardest hit by Alzheimer’s—the number of sticky amyloid plaques dropped by about 40%. While this effect wasn’t observed everywhere (plaques in the neocortex, for example, remained), it points to the importance of region-specific mechanisms.
- Preserved Synaptic Connections: The brain’s ability to process and store information hinges on the integrity of its synapses. Keeping more of these connections intact appears to underlie the behavioral improvements seen in the mice.
- Improved Spatial Learning: Perhaps most excitingly, mice lacking Centaurin-α1 performed better in spatial memory tests, closely resembling healthy controls.
Why is Centaurin-α1 So Central?
The broad improvements prompted questions: is Centaurin-α1 a master regulator of many damaging pathways in Alzheimer’s? To probe this, the researchers analyzed how thousands of genes changed when Centaurin-α1 was absent. They discovered that the overall “molecular environment” of the brain in their modified mice began to resemble healthy brain tissue. Genes that Alzheimer’s disease pushes higher dropped back toward normal, while those that are usually suppressed rebounded.
Senior author Dr. Ryohei Yasuda speculates, “We think that Centaurin-α1 may play a multifunctional role in regulating brain signaling, gene expression, metabolic processes, neuroinflammation, amyloid processing, and the stability of neural connections.” In other words, Centaurin-α1 is not just a bystander or minor participant—it may be orchestrating several key players in the Alzheimer’s disease process.
A Potential Path to Future Treatments
The implications of these findings are considerable. By simply removing Centaurin-α1, the mice were, to a notable degree, protected from a range of Alzheimer’s-like effects. This raises the hope that blocking this protein’s function—possibly with drugs in the future—could benefit people, too.
But important questions remain.
- Does blocking Centaurin-α1 after Alzheimer’s symptoms appear provide the same benefit as removing it from birth?
- Why were some regions, like the neocortex, resistant to the beneficial effects seen in the hippocampus?
- And would humans respond in the same way as mice?
The research team has begun tackling some of these questions, including whether interventions later in life might still help slow the disease’s progression. Intriguingly, they recently found that blocking Centaurin-α1 also reduced symptoms in an animal model of multiple sclerosis (MS), suggesting it could be relevant for other neurodegenerative diseases as well.
The Road Ahead
For Alzheimer’s researchers and families alike, these results are a reminder that sometimes, targeting the right molecular lever can shift the entire machinery of disease. With Centaurin-α1 now in the crosshairs, the path is set for deeper exploration—testing targeted inhibitors, probing its mechanisms in brain health and disease, and, perhaps, one day offering those living with Alzheimer’s new hope.
Reference
Szatmari, E., et al. (2024). Lack of ADAP1/Centaurin-α1 Ameliorates Cognitive Impairment and Neuropathological Hallmarks in a Mouse Model of Alzheimer’s Disease. eNeuro.
Source: Max Planck Institute. "Blocking a Key Protein Greatly Reduces Alzheimer’s Damage." Neuroscience News. https://neurosciencenews.com/alzheimers-protein-reduction-30023/
