Alzheimer’s May Trigger Brain’s Own Synapse Pruning Mechanism

Alzheimer’s disease may not just destroy memories—it could be tricking the brain into erasing them itself. Recent research suggests that the accumulation of amyloid beta and inflammatory signals converge on a molecular switch known as the LilrB2 receptor, which activates neurons to prune synapses.

This mechanism links two major Alzheimer’s theories—amyloid pathology and neuroinflammation—into a shared pathway for synaptic loss.

C4d, a protein involved in the complement cascade, binds to LilrB2 and exacerbates synapse removal in mice. This interaction demonstrates how immune-related processes can directly influence neuronal connectivity.

Notably, neurons themselves appear to play an active role in this pruning, challenging the long-held assumption that glial cells are the primary drivers of synapse elimination.

Carla Shatz, a neuroscientist at Stanford University, has critiqued the limited efficacy of current amyloid-targeting drugs, describing their outcomes as “not that well” with significant side effects. She emphasizes that targeting LilrB2 could offer a more precise therapeutic strategy by addressing the downstream consequences of amyloid and inflammation.

“Neurons aren’t innocent bystanders. They are active participants,” Shatz stated, highlighting the need to shift focus from merely removing plaques to modulating synaptic pruning pathways.

While these findings suggest a promising avenue for intervention, the study’s authors caution that further research is required to validate LilrB2 as a viable target in human models.

The team notes that the complement cascade’s role in healthy brain development and disease remains incompletely understood, underscoring the complexity of translating these insights into clinical applications.