Brain’s Own Defense System May Drive Alzheimer’s Memory Loss

Stanford University researchers have identified a surprising mechanism behind Alzheimer's memory loss: the disease may trick the brain into destroying its own neural connections through a single molecular receptor. The findings suggest that neurons aren't simply passive victims of Alzheimer's damage but actively respond to signals that command them to eliminate synapses, the connections that allow brain cells to communicate.

The research centers on a receptor called LilrB2, a molecular gatekeeper that controls whether neurons prune their synapses. Scientists discovered that both amyloid beta—a toxic protein that accumulates in Alzheimer's brains—and inflammatory molecules can activate this receptor, triggering neurons to strip away their own connections. This shared pathway suggests that Alzheimer's may attack memory through multiple routes that converge on the same biological mechanism.

Background

The study builds on decades of research into how the brain naturally maintains itself. Synaptic pruning is a normal process where the brain removes unused or damaged connections between neurons. During childhood development and throughout life, this pruning helps the brain stay efficient and responsive. However, in Alzheimer's disease, researchers believe this protective mechanism goes wrong.

Scientist Carla Shatz and her team at Stanford have studied the LilrB2 receptor since 2006, when they first discovered its role in synaptic pruning during normal brain development. In 2013, the same team made a critical connection: they showed that amyloid beta can bind directly to LilrB2, triggering neurons to remove synapses. Even more importantly, when researchers removed the receptor genetically in laboratory mice with Alzheimer's symptoms, the animals were protected from memory loss.

These earlier findings suggested that blocking LilrB2 might prevent the memory destruction seen in Alzheimer's. But the recent research reveals a more complex picture. The team discovered that inflammation—a hallmark of Alzheimer's disease—activates the same receptor through a different molecular pathway.

Key Details

The researchers screened various inflammatory molecules to determine which ones could bind to the LilrB2 receptor. They identified a protein fragment called C4d, part of the body's complement cascade, a system that normally helps fight infection and clear damaged cells. When C4d attached to the LilrB2 receptor, it appeared capable of triggering synapse loss.

To test this theory, the team injected C4d directly into the brains of healthy mice. The results were striking. The injection stripped synapses from neurons—essentially causing the same damage seen in Alzheimer's disease, but through inflammation rather than amyloid buildup.

"There's an entire set of molecules and pathways that lead from inflammation to synapse loss that may not have received the attention they deserve," said Shatz, who is also a professor of biology and neurobiology at Stanford.

This discovery suggests that scientists may have been focusing too narrowly on amyloid beta when treating Alzheimer's. Current FDA-approved drugs like lecanemab and aducanumab work by removing amyloid plaques from the brain. While these drugs slow cognitive decline, they don't restore lost memory or reverse damage already done. The new research indicates that even if scientists successfully clear all amyloid from an Alzheimer's brain, the inflammatory pathways that trigger synapse loss remain active.

A Shared Mechanism

The convergence of amyloid beta and inflammatory molecules on the same receptor reveals an important insight: Alzheimer's disease may attack memory through multiple entry points that all lead to the same destination. Both pathways activate LilrB2, which then commands neurons to eliminate their connections. This means that blocking amyloid alone may not be enough to stop memory destruction if inflammation continues unchecked.

The researchers also found that removing the LilrB2 receptor genetically protected mice from memory loss, even in the presence of amyloid accumulation. This suggests that the receptor itself, rather than the triggers that activate it, is the critical control point.

What This Means

The implications for Alzheimer's treatment could be substantial. Rather than focusing exclusively on clearing amyloid plaques, researchers might develop drugs that block the LilrB2 receptor or the inflammatory molecules that activate it. Such an approach could protect synapses from being pruned away, potentially preserving memory even if amyloid remains in the brain.

The timing of this discovery coincides with growing recognition that inflammation plays a central role in Alzheimer's disease. Other recent research has identified additional inflammatory pathways that might be targeted therapeutically. One team has developed a compound that inhibits an enzyme linked to brain inflammation in people carrying the APOE4 gene, a major genetic risk factor for Alzheimer's. Another group identified a natural molecule that appears to restore memory function in Alzheimer's models by jumpstarting the brain's electrical rhythms.

These parallel discoveries suggest that the field is moving toward treatments that address the underlying damage mechanisms in Alzheimer's rather than simply targeting amyloid accumulation. By protecting synapses from being destroyed, researchers hope to preserve or even restore memory function in people with the disease.

The Stanford team emphasizes that their findings point toward a new therapeutic direction. Rather than asking how to remove harmful proteins from the brain, the question becomes: how can we prevent neurons from destroying their own connections? The answer may lie in blocking the molecular switches that command that destruction.