Alzheimer's discovery reveals brain cleaning gone wrong
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A gene responsible for compacting trash inside the brain appears to be a key player in Alzheimer's disease, and doctors may be able to target it to better treat or help prevent the devastating condition, new UVA Health research suggests.
Researchers led by John Lukens, Ph.D., investigated the function of the CASS4 gene after it was identified as an Alzheimer's risk factor in numerous studies. They found that it helps direct brain-cleaning immune cells called microglia, and when the gene's proper function was disrupted, the effects were dire: The microglia could no longer effectively respond to harmful plaques forming in the brain, and they were far less able to contain and compact the toxins that make up those plaques. That allowed the plaques to grow more quickly and spread more aggressively.
"These findings break new ground in our understanding of how this genetic risk factor contributes to Alzheimer's disease," said Lukens, director of UVA's Harrison Family Translational Research Center in Alzheimer's and Neurodegenerative Diseases. "Our work further suggests that defective CASS4 activity may serve as an early-onset biomarker to detect Alzheimer's and that therapeutic strategies which boost its function may offer a much-needed approach to treat this devastating brain disease."
Lukens and his colleagues have published their new findings in the Journal of Experimental Medicine.
Alzheimer's development
Alzheimer's affects more than 6 million Americans. It is a progressive disease that worsens over time, robbing people of their memories to the point they can forget their own children. It is the sixth-leading cause of death in the United States.
The development of Alzheimer's is accompanied by the buildup of sticky clusters of proteins inside the brain known as amyloid-beta plaques, as well as twisted tangles of tau proteins. Recent research has shown that the immune system—specifically microglia—may be playing a central role in this.
When functioning properly, microglia form protective barriers around the amyloid-beta plaques and compact them down as small as possible to minimize the harm they can cause. But Lukens' new research suggests that faulty or ineffective variants of the gene can leave the brain inadequately defended. In lab mice, this impaired the microglia, caused amyloid-beta buildup, harmed nerve cells called neurons and sent the mice into cognitive decline.
"Despite CASS4 being an Alzheimer's risk gene, really nothing is known about what this gene does or how it affects the brain during disease. Our lab sought to address this major knowledge gap with this paper," said Addie Walsh, UVA physiology graduate student and first author of the paper. "These are important findings because they give us new insight into how this understudied AD risk gene functions in the brain and suggest that CASS4 may normally help microglia respond to amyloid pathology."
The loss of CASS4 triggered a cascade of changes in gene activity that may be contributing not just to Alzheimer's but to other neurodegenerative diseases as well, the researchers note.
Based on their results, the scientists suspect that doctors may be able to develop ways to target the gene or the microglia in the brain to help slow or prevent the development of Alzheimer's.
"We are now actively exploring potential roles for CASS4 in multiple other neurodegenerative disorders and developing novel strategies to therapeutically target it," said Lukens, of the Department of Neuroscience at the University of Virginia School of Medicine.
"Many in the field initially presumed that CASS4 was likely functioning in neurons to influence Alzheimer's. Our findings shift this paradigm by proving that CASS4 predominantly acts through the immune system. This is particularly exciting, as it has only been in recent years that immune-targeting strategies have been considered for the treatment of neurodegenerative diseases, and this remains an untapped therapeutic avenue with tremendous potential."
Publication details
Adeline E. Walsh et al., Alzheimer's genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis, Journal of Experimental Medicine (2026). DOI: 10.1084/jem.20260104
Journal information: Journal of Experimental Medicine
Key medical concepts
Alzheimer's DiseaseMicrogliaCognitive Declines
Clinical categories
NeurologyClinical genetics Provided by University of Virginia Who's behind this story?
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