Genetic Deficiency Aggravates Alzheimer’s Disease Progression

In both human and animal studies, CX3CR1 has been identified to be a key checkpoint regulator of microglial activation in Alzheimer's disease, but it’s exact role in modulating Aβ driven neurodegeneration and accumulating hyperphosphorylated tau is not well understood. That’s why researchers at the Indiana University School of Medicine investigated how removing this gene in immune cells shaped the progression of Alzheimer's disease.

The team’s study, published in Molecular Degeneration, reveals that deleting the microbial gene CX3CR1 in animal models with Alzheimer's resulted in considerably more plaques in the brain. Additionally, the team found that this gene impaired the movement of microglia towards the plaques, thus working against one of the brain’s specialized immune cells.

“This investigation shows that microglia in Alzheimer’s disease become dysfunctional earlier in the disease course in the absence of CX3CR1, and this dysfunction results in the cascade of neurotoxic events in the brain,” says first author Shweta Puntambekar, MS, PhD, assistant research professor of medical and molecular genetics. “For the larger research community, this research pinpoints how we can target this cell type early in the disease in order to modulate how the disease progresses in the brain and ultimately modulate cognitive outcomes in Alzheimer’s disease.”

Back in 2020, Puntambekar and her colleagues received a grant worth $3 million from the National Institute on Aging to study the role of CX3CR1 in Alzheimer’s disease. Their work examined the connection between amyloid beta and tau in the brain, both of which are hallmark proteins associated with neurodegenerative diseases. When amyloid beta proteins clump together, they create “plaques” that can destroy nerve connections, increase tau production, and make it harder for microglia to act as the brain’s first line of defense.

“The study has made a connection not just between amyloid and tau, but how microglia can shape the entire disease process,” states Puntambekar. She notes that some of those species of amyloid beta aren’t deposited in the brain as “insoluble” plaques, but rather accumulate in the brain as soluble plaques and have been shown to also be associated with cognitive decline. These species were increased in the absence of CX3CR1, she adds.

While most therapies targeting amyloid beta proteins focus on insoluble plaques, these drugs have long been shown to be ineffective in clinical trials. “With this new data set, we can now start asking if the limited clinical efficiencies of Alzheimer’s disease therapies are due to not targeting the correct species of amyloid beta and whether we should start targeting other soluble species to get better cognitive outcomes,” Puntambekar says.