Summary: New experimental results show that removing Centaurin‑α1, a protein found at higher levels in Alzheimer’s disease, markedly reduces inflammation, lowers plaque accumulation in the hippocampus, and lessens cognitive deficits in a widely used mouse model. Deleting this protein restored several disrupted molecular pathways, preserved synaptic connections in the hippocampus, and improved spatial learning performance.
Although the decrease in amyloid plaques differed by brain region, the overall improvements indicate Centaurin‑α1 as a promising target for therapeutic development. Ongoing work will test whether reducing Centaurin‑α1 later in life—rather than deleting it from birth—can also slow disease progression.
Key Facts
- Protein Removed, Damage Reduced: Genetic deletion of Centaurin‑α1 reduced markers of neuroinflammation and cut hippocampal plaque load by roughly 40%.
- Cognitive Benefits: Mice lacking Centaurin‑α1 retained more synaptic connections and performed better in spatial learning tasks than untreated Alzheimer’s model mice.
- Therapeutic Potential: Removing Centaurin‑α1 partially normalized altered gene expression patterns, suggesting the protein influences multiple pathways linked to Alzheimer’s pathology.
Source: Max Planck Institute
New research published in the journal eNeuro evaluated whether eliminating a protein that is elevated in Alzheimer’s brains could prevent or reduce neuropathology and cognitive symptoms in a mouse model of the disease.
“Previous work from our group and others indicated that Centaurin‑α1 plays a role in neuronal damage associated with Alzheimer’s,” said lead author Dr. Erzsebet Szatmari. To test whether the protein contributes to disease progression and whether it could serve as a therapeutic target, the team removed Centaurin‑α1 genetically in an established mouse model.
The researchers used the J20 transgenic mouse, a well-characterized model that overexpresses mutated forms of human amyloid precursor protein (APP) linked to familial Alzheimer’s disease. J20 mice develop many features observed in human patients, including neuroinflammation, amyloid plaque accumulation, synapse loss, and deficits in spatial memory and learning.
Removing Centaurin‑α1 reduces disease-related damage
To determine Centaurin‑α1’s role, the team bred J20 mice with Centaurin‑α1 knockout animals and compared pathology and behavior across genotypes. One of the earliest signs in J20 mice was widespread neuroinflammation; mice lacking Centaurin‑α1 showed markedly reduced inflammatory markers.
Removal of Centaurin‑α1 also decreased amyloid plaque burden, particularly in the hippocampus, where plaque area fell by about 40%. This reduction was not observed uniformly: plaque levels in the neocortex remained similar, indicating region-specific effects and suggesting that effective therapies may need to address multiple mechanisms across brain regions.
Beyond inflammation and plaques, deleting Centaurin‑α1 partially protected synapses in the hippocampus, a structure essential for spatial navigation and memory. Correspondingly, J20 mice lacking Centaurin‑α1 performed better in spatial learning tests, showing partial rescue of cognitive deficits.
Centaurin‑α1 as a therapeutic candidate
“The behavioral improvements observed in J20 mice lacking Centaurin‑α1 support the idea that this protein contributes to cognitive decline and may be a viable therapeutic target,” said Szatmari. However, she emphasized that the mechanisms by which Centaurin‑α1 exacerbates disease remain to be fully defined.
To explore how Centaurin‑α1 influences disease biology, the team compared gene expression profiles from wild-type mice, J20 mice, and J20 mice without Centaurin‑α1. Many gene expression changes produced by APP overexpression in J20 mice were reversed or normalized when Centaurin‑α1 was removed, consistent with a partial molecular rescue of disease phenotypes.
Senior author Dr. Ryohei Yasuda noted that Centaurin‑α1 likely affects multiple signaling pathways that influence gene expression, metabolism, inflammation, amyloid processing, and synaptic function. “Aberrant Centaurin‑α1 signaling may amplify several disease-relevant processes,” he explained.
While additional studies are required to determine whether targeting Centaurin‑α1 would benefit human patients, the current findings identify it as a promising candidate for further preclinical development. The research team is now testing whether reducing Centaurin‑α1 activity in adulthood—rather than deleting it from development—can also delay or mitigate disease progression.
Interestingly, prior work from the group found that loss of Centaurin‑α1 lessened symptoms in a mouse model of multiple sclerosis, suggesting the protein’s role in neurodegeneration may extend beyond Alzheimer’s disease.
Funding: This work was supported by the BrightFocus Foundation, Community Foundation of the Palm Beaches, the National Institute on Aging (NIA), the Max Planck Foundation, ECU startup funds, and ECU URCA awards. The content is the authors’ responsibility and does not necessarily reflect the funders’ official views.
Key Questions Answered:
A: Neuroinflammation decreases, hippocampal amyloid plaque burden falls, synaptic connections are better preserved, and spatial learning improves.
A: Deleting Centaurin‑α1 partially restores disrupted gene expression and reduces several Alzheimer’s-related pathological features, implying it influences multiple disease pathways.
A: No. The study observed significant plaque reduction in the hippocampus but not in the neocortex, indicating region-specific mechanisms and the potential need for combination approaches.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full.
- Additional context was provided by editorial 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, also known as ADAP1 or Centaurin‑α1 (CentA1), is a brain-enriched, evolutionarily conserved regulator of Arf6 GTPase activity and Ras anchoring. CentA1 contributes to dendritic outgrowth and branching, synapse formation, and axonal polarity by modulating actin cytoskeleton dynamics.
CentA1 is upregulated and associates with amyloid plaques in postmortem human Alzheimer’s brains, implicating it in disease progression. To investigate its role in neurodegeneration, the authors crossed CentA1 knockout mice with the J20 AD model and assessed behavioral, neuropathological, and gene expression changes in male mice.
J20 animals displayed impaired spatial memory in the Morris water maze, a deficit that was rescued in J20xKO mice lacking CentA1. Neuropathological features of AD—such as amyloid plaque deposition and neuroinflammation—were also significantly reduced in J20xKO mice. Comparative gene expression analysis showed that the transcriptional changes caused by APP overexpression in J20 mice were largely anticorrelated with changes produced by CentA1 deletion, consistent with phenotypic rescue.
Together, these findings indicate that CentA1 contributes to the development of AD-like phenotypes in this model and suggest that targeting CentA1 signaling could offer therapeutic benefit for prevention or treatment of Alzheimer’s disease.