Alzheimer’s disease may initiate memory loss by prompting the brain to eliminate its own synaptic connections. A team of researchers at the Wu Tsai Neurosciences Institute at Stanford University has uncovered a potential mechanism linking amyloid beta and inflammation, suggesting that both converge on a common receptor responsible for synapse pruning. This finding, published on January 26, 2026, in the Proceedings of the National Academy of Sciences, could illuminate new avenues for treatment.
The study, led by Carla Shatz, the Sapp Family Provostial Professor, highlights a significant aspect of Alzheimer’s disease: the destruction of neural connections that enable memory storage and recollection. While amyloid beta, a protein fragment known to accumulate in the brains of Alzheimer’s patients, has been a focal point of research, other factors such as tau proteins and inflammation have also been implicated in the disease’s progression.
Connecting Two Major Theories
Researchers have established a link between two of the most prominent theories regarding the origins of Alzheimer’s. In their investigation, they discovered that both amyloid beta and inflammatory responses act through the same molecular pathway, targeting a receptor that signals neurons to eliminate synapses. This insight was made possible through the collaboration of scientists including first author Barbara Brott, a research scientist in Shatz’s laboratory.
The work received partial funding from the Knight Initiative for Brain Resilience, aimed at re-evaluating the biological underpinnings of neurodegenerative diseases.
The Role of LilrB2
A critical component of this study revolves around a receptor called LilrB2, which has been the subject of Shatz’s research for years. Previous studies revealed that the mouse variant of LilrB2 is vital for synaptic pruning, a normal process that occurs during brain development and learning. In 2013, Shatz’s team determined that amyloid beta binds to LilrB2, triggering synapse elimination. Remarkably, genetic removal of this receptor in mice protected them from memory loss in an Alzheimer’s model.
In addition, the researchers explored the complement cascade, an immune process that normally helps the body eliminate pathogens and damaged cells. Chronic inflammation is known to heighten Alzheimer’s risk, and recent findings have connected the complement cascade to excessive synaptic pruning. This led the team to investigate whether inflammatory molecules might interact with LilrB2 similarly to amyloid beta.
In their tests, the researchers identified the protein fragment C4d as a potential contributor to synapse loss. When injected into the brains of healthy mice, C4d caused significant synaptic removal, challenging prior assumptions regarding its role in neurobiology.
The comprehensive nature of these findings suggests that both amyloid beta and inflammation may induce synapse loss through a shared biological mechanism. Shatz emphasized that this could necessitate a reevaluation of how Alzheimer’s disease leads to cognitive decline, noting that there exist pathways linking inflammation and synapse loss that have not received adequate attention.
Implications for Future Treatments
This new perspective carries important implications for Alzheimer’s treatment strategies. Current FDA-approved interventions primarily target amyloid plaques, but Shatz cautioned that these therapies have shown limited effectiveness and carry considerable side effects.
“Busting up amyloid plaques hasn’t worked that well, and there are a lot of side effects,” Shatz stated, highlighting issues such as headaches and brain bleeding. “Even if they worked well, you’re only going to solve part of the problem.”
Instead, targeting receptors like LilrB2, which directly influence synapse removal, may offer a more effective approach. By focusing on the preservation of synaptic connections, researchers could potentially safeguard memory itself.
The study included contributions from several authors, including Aram Raissi, Monique Mendes, Caroline Baccus, Jolie Huang, and Kristina Micheva from Stanford University and Jost Vielmetter from the California Institute of Technology. Funding support was provided by the National Institutes of Health and various foundations dedicated to brain research.
In summary, this research sheds light on the active role neurons play in Alzheimer’s disease, challenging the notion that glial cells are the primary agents in synaptic loss. As the scientific community continues to explore this complex disease, the findings may pave the way for innovative treatments that can meaningfully impact the lives of those affected by Alzheimer’s.
