It seems like every other day a new report comes out linking another gene variant to Alzheimer’s disease.
CASS4, a member of a family of scaffold genes, is one of these genes. As far as genes go, its function seems fairly mundane. It codes for a protein involved in intracellular infrastructure and adhesion. However, several studies have tied single nucleotide polymorphisms in CASS4 to an increased risk of developing Alzheimer’s. Now a new study published in the Journal of Experimental Medicine is helping explain why.
“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,” study author Addie Walsh of the University of Virginia explained in a statement. “Our lab sought to address this major knowledge gap with this paper.”
Walsh and a team of neuroscientists used mice as a model organism to study the gene. They crossed transgenic mice with no CASS4 gene with transgenic mice engineered to manifest amyloid plaques, clumps of sticky beta-amyloid protein that build up in the brains of those with Alzheimer’s. They then put their offspring through a battery of tests to investigate the activity of CASS4.
The mice had larger and more numerous amyloid plaques in their brains and more damaged neurons, and cognitive tests showed they struggled to form new memories. To zoom in at the cellular level, the team looked at how the loss of CASS4 affected the brain cells where they were expressed: microglia. These are the brain’s resident immune cells, responsible for clearing toxins, fighting pathogens, and clearing away dead cells. Essentially they’re the brain’s little trash collectors.
Curiously, the lack of CASS4 didn’t make the microglia any less numerous, active, or worse at collecting amyloid. When microglia are functioning normally, they surround the plaques, forming a protective barrier and compacting them. But without CASS4, they struggled to do this important job.
According to the team, these findings may allow doctors to detect Alzheimer’s sooner—an important development considering currently available pharmaceuticals only slow the disease down—and could lead to new treatments. “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,” study author John Lukens said.
It could also advance treatments for other diseases. CASS4 isn’t just linked to Alzheimer’s; it’s been implicated in lung cancer, cystic fibrosis, thrombosis, and more.
Genes with mundane jobs can cause a lot of damage when something goes wrong.
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Lead Image: Syed07 / Wikimedia Commons
