Brain inflammation, a vital part of the body’s immune defense, takes on a harmful role in Alzheimer’s disease. Unlike the acute, short-lived inflammation that combats infections, the inflammation seen in Alzheimer’s becomes chronic and persistent, contributing to the progression of dementia. Researchers have long been trying to understand the underlying causes of this persistent inflammation.
New research sheds light on key differences in the way the brain’s immune system responds to Alzheimer’s disease compared to a bacterial infection. The findings will be presented at the 69th Biophysical Society Annual Meeting, set to take place in Los Angeles from February 15 to 19, 2025.
The study focuses on the immune system’s reaction to amyloid-beta (Aβ) plaques, a hallmark of Alzheimer’s, and compares it to the immune response triggered by bacterial toxins. “Bacteria cannot enter our brain due to the blood-brain barrier,” explained Arpan Dey, PhD, a postdoctoral associate in the lab of Professor David Klenerman at the University of Cambridge. “However, small proteins may behave similarly to bacteria in the brain, potentially causing neuroinflammation and contributing to dementia.”
Dey and his team used an immune cell model to expose the cells to Aβ aggregates or lipopolysaccharide (LPS), a component of bacterial cell walls that triggers a strong immune reaction. The researchers specifically examined the formation of structures called myddosomes, which play a critical role in initiating inflammation.
The study found that larger Aβ aggregates induced greater myddosome formation in immune cells. Smaller Aβ clumps, even after prolonged exposure, did not elicit this response. This suggests that the size of Aβ aggregates is a key factor in activating the brain’s immune system in Alzheimer’s disease.
In comparison, LPS triggered a faster and more intense myddosome response than even the large Aβ aggregates. This difference in the timing and intensity of immune activation may help explain why Alzheimer’s inflammation becomes chronic, while the immune response to bacterial infections is typically swift and resolves quickly.
“Our findings highlight an important distinction in how the brain’s immune system reacts to bacterial infections versus Aβ clumps,” said Dey. “The slower, sustained immune activation triggered by large Aβ aggregates may be responsible for the chronic inflammation seen in Alzheimer’s.”
The next phase of the research will focus on identifying markers of myddosome formation in blood samples from individuals with dementia and brain samples from the UK Brain Bank.
By understanding the mechanisms behind inflammation in Alzheimer’s, the team hopes to contribute to the development of new therapies aimed at targeting chronic inflammation, potentially slowing disease progression.
“This work opens up exciting possibilities for drug discovery,” Dey concluded. “By targeting the inflammatory pathways involved in Alzheimer’s, we could develop treatments for this disease and other neurodegenerative conditions.”
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