Researchers have uncovered how amyloid beta and inflammation may both trigger synapse pruning in Alzheimer's disease through a common receptor, potentially offering new treatment avenues. The findings challenge the notion that neurons are passive in this process, showing they actively erase their own connections. Led by Stanford's Carla Shatz, the study suggests targeting this receptor could preserve memory more effectively than current amyloid-focused drugs.
Alzheimer's disease progressively dismantles the brain's neural networks, leading to severe memory impairment. While amyloid beta buildup has long been implicated, other factors like chronic inflammation also play key roles. A new study published in the Proceedings of the National Academy of Sciences bridges these ideas, showing that both amyloid beta and inflammation converge on the LilrB2 receptor to signal neurons to prune synapses—the junctions essential for communication between brain cells.
The research, spearheaded by Carla Shatz, the Sapp Family Provostial Professor at Stanford University, and first author Barbara Brott, builds on prior discoveries. In 2006, Shatz's team identified the mouse equivalent of LilrB2 as crucial for synaptic pruning during development and learning. By 2013, they demonstrated that amyloid beta binds to this receptor, prompting synapse removal, and that genetically eliminating it protected mice from memory deficits in an Alzheimer's model.
Extending this, the team explored the complement cascade, an immune response linked to excessive pruning in neurological disorders. Screening revealed that the protein fragment C4d binds strongly to LilrB2. When injected into healthy mice brains, C4d rapidly stripped synapses from neurons. "Lo and behold, it stripped synapses off neurons," Shatz remarked, noting the surprise since C4d was previously considered non-functional.
These results indicate a unified pathway for memory loss, with inflammation's molecules like C4d mimicking amyloid beta's effects. Importantly, the study shifts focus from glial cells to neurons themselves: "Neurons aren't innocent bystanders," Shatz emphasized. "They are active participants."
Current FDA-approved treatments target amyloid plaques but yield modest results alongside risks such as headaches and brain bleeding. Shatz argues that addressing LilrB2 directly might safeguard synapses and memory more comprehensively. "Busting up amyloid plaques hasn't worked that well... you're only going to solve part of the problem."
Funded partly by the National Institutes of Health and the Knight Initiative for Brain Resilience, the work involved collaborators from Stanford and the California Institute of Technology, using human Alzheimer's tissue from the University of California, San Francisco's brain bank.
