Summary: New findings show that removing Centaurin-α1, a protein elevated in Alzheimer’s disease, significantly reduces inflammation, plaque buildup, and cognitive deficits in a well-established mouse model. Eliminating this protein normalized several brain pathways, protected neural connections in the hippocampus, and improved spatial learning.
Although plaque reduction varied across brain regions, the overall improvements point to Centaurin-α1 as a potential therapeutic target. Researchers now aim to determine whether reducing the protein in adulthood could also slow disease progression.
Key Facts
- Protein Removed, Damage Reduced: Eliminating Centaurin-α1 reduced neuroinflammation and cut hippocampal plaque load by about 40%.
- Cognitive Benefits: Mice lacking the protein showed better preservation of neural connections and improved spatial learning.
- Therapeutic Potential: Normalization of gene expression patterns suggests Centaurin-α1 may regulate multiple Alzheimer’s-related processes.
Source: Max Planck Institute
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.
Funding: 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.
Key Questions Answered:
A: Neuroinflammation decreases, amyloid plaques drop in the hippocampus, neural connections are better preserved, and spatial learning improves.
A: Removing it normalizes disrupted gene expression patterns and reduces multiple Alzheimer’s-related problems, suggesting it influences several disease pathways.
A: No—plaques decreased significantly in the hippocampus but not in the neocortex, indicating region-specific mechanisms and the possible need for multipronged therapies.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this Alzheimer’s disease research news
Author: Lesley Colgan
Source: Max Planck Institute
Contact: Lesley Colgan – Max Planck Institute
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Lack of ADAP1/Centaurin-α1 Ameliorates Cognitive Impairment and Neuropathological Hallmarks in a Mouse Model of Alzheimer’s Disease” by Erzsebet Szatmari et al. eNeuro
Abstract
Lack of ADAP1/Centaurin-α1 Ameliorates Cognitive Impairment and Neuropathological Hallmarks in a Mouse Model of Alzheimer’s Disease
ArfGAP, with dual PH domain-containing protein 1/Centaurin-α1 (ADAP1/CentA1), is a brain-enriched and highly conserved Arf6 GTPase-activating and Ras-anchoring protein. CentA1 is involved in dendritic outgrowth and arborization, synaptogenesis, and axonal polarization by regulating the actin cytoskeleton dynamics.
CentA1 upregulation and association with amyloid plaques in the human Alzheimer’s disease (AD) brain suggest the role of this protein in AD progression.
To understand the role of CentA1 in neurodegeneration, we crossbred CentA1 knock-out (KO) mice with the J20 mouse model of AD. We evaluated AD-associated behavioral and neuropathological hallmarks and gene expression profiles in J20 and J20 crossed with CentA1 KO (J20xKO) male mice to determine the impact of eliminating CentA1 expression on AD-related phenotypes.
Spatial memory assessed by the Morris water maze test showed significant impairment in J20 mice, which was rescued in J20xKO mice. Moreover, neuropathological hallmarks of AD, such as amyloid plaque deposits and neuroinflammation, were significantly reduced in J20xKO mice.
To identify potential mediators of AD phenotype rescue, we analyzed differentially expressed genes between genotypes. We found that changes in the gene profile by deletion of CentA1 from J20 (J20xKO vs J20) were anticorrelated with changes caused by APP overexpression (J20 vs wild type), consistent with rescue of J20 phenotypes by CentA1 KO.
In summary, our data indicate that CentA1 is required for the progression of AD phenotypes in this model and that targeting CentA1 signaling might have therapeutic potential for AD prevention or treatment.
