Alzheimer’s disease is known for one devastating effect above all others.it steadily destroys brain cells and the connections between them, breaking down the neural networks that allow us to store and recall memories.
What remains far less certain is how this destruction begins. One leading clarification focuses on amyloid beta, a protein fragment that can accumulate in the brain and harm neurons. But scientists have also linked Alzheimer’s to many other factors, including tau proteins, lysosomes, chronic inflammation, immune cells called microglia, and additional biological processes.
A Possible Link Between Two Major Theories
Researchers now believe thay may have found a way to connect two of the moast prominent ideas about how Alzheimer’s develops. In a study published in Proceedings of the National Academy of Sciences,scientists report new evidence that amyloid beta and inflammation may act through the same molecular pathway. Both appear to converge on a specific receptor that signals neurons when to eliminate synapses, the contact points that allow brain cells to communicate.
The research was lead by Wu Tsai Neurosciences Institute affiliate Carla Shatz, the Sapp Family Provostial Professor, along with first author Barbara Brott, a research scientist in Shatz’s laboratory. The work received partial support from a Catalyst Award from the Knight Initiative for Brain Resilience, a program focused on reexamining the basic biology behind neurodegenerative diseases such as Alzheimer’s.
The Role of a Synapse Pruning Receptor
One major component of the study builds on earlier work involving a receptor known as LilrB2. Shatz has studied this molecule for years. In 2006, she and her colleagues discovered that the mouse version of LilrB2 plays an essential role in synaptic pruning, a normal process during brain advancement and learning in adulthood.
Later findings connected this same receptor to alzheimer’s. In 2013, Shatz’s team showed that LilrB2 levels increase in the brains of mice with Alzheimer’s-like symptoms. This suggested the receptor might be involved in the disease process,but the exact mechanism remained unclear.
Amyloid Beta and Inflammation Converge
The new study reveals that both amyloid beta and inflammation can activate LilrB2. when amyloid beta builds up in the brain, it triggers an immune response, causing microglia to release inflammatory signals. These signals, along with amyloid beta itself, bind to LilrB2, telling synapses to retract.
“We found that amyloid beta and inflammation are ‘talking’ to the same receptor,” Shatz explained. “this suggests that they may be working together to drive synaptic loss in Alzheimer’s disease.”
Blocking LilrB2 protects Synapses
To test this idea, the researchers genetically engineered mice to lack LilrB2. These mice were protected from synapse loss even when exposed to amyloid beta and inflammation. This provides strong evidence that LilrB2 is a key mediator of synaptic damage in Alzheimer’s.
Implications for treatment
The findings suggest that blocking LilrB2 could be a potential therapeutic strategy for Alzheimer’s disease. Though, Shatz cautions that LilrB2 also plays vital roles in normal brain function, so simply blocking it could have unintended consequences.
“We need to find a way to selectively block LilrB2 in the context of Alzheimer’s disease,” she said. “That’s the challenge now.”
The researchers are currently exploring ways to target LilrB2 more specifically, such as developing antibodies that only bind to the receptor when it’s activated by amyloid beta or inflammation.
