In youth, synaptic connections associated with vision remain plastic, and they usually become less so with maturity. But not always: If the gene for a particular receptor is absent, the wiring for visual parts of the brain stay flexible. The absence of this gene—or at least interventions curbing this gene’s effects—could sustain synaptic flexibility more generally. That, at least, is the hope behind scientists’ interest in a receptor first identified in research on the visual system. This receptor has now been shown to bind with β-amyloid, a protein fragment that accumulates in the brain during Alzheimer’s disease. If this receptor can be blocked, perhaps Alzheimer’s can be slowed or even prevented.
In a paper published September 19 in Science, a team of scientists based in Stanford University led by Carla Shatz, Ph.D., report that the LilrB2 receptor in humans and the PirB receptor in mice can physically partner with β-amyloid, triggering a harmful chain reaction in brain cells. However, in a mouse model of Alzheimer’s, mice known to lack the gene for PirB were less vulnerable. They did not experience this chain reaction, and they had reduced memory loss.
During development, the eyes compete to connect within a limited territory of the brain—a process known as ocular dominance plasticity. The competition takes place during a limited time in early life. If visual experience through one eye is impaired during that time—for example, by a congenital cataract (present from birth)—it can permanently lose territory to the other eye.
“Ocular dominance is a classic example of how a brain circuit can change with experience,” Dr. Shatz said. “We’ve been trying to understand it at a molecular level for a long time.”
Dr Shatz’s search eventually led to PirB, a protein on the surface of nerve cells in the mouse brain. She discovered that mice without the gene for PirB have an increase in ocular dominance plasticity. In adulthood, when the visual parts of their brains should be mature, the connections there are still flexible. This established PirB as a “brake on plasticity” in the healthy brain, Dr. Shatz said.
It wasn’t long before Dr. Shatz began to wonder if PirB might also put a brake on plasticity in Alzheimer’s disease. This curiosity led to the current study, “Human LilrB2 Is a β-Amyloid Receptor and Its Murine Homolog PirB Regulates Synaptic Plasticity in an Alzheimer’s Model.”
Dr. Shatz’s team started by repeating the genetic experiment that Dr. Shatz had done in normal mice, but this time they deleted the PirB gene in the Alzheimer’s mice. By about nine months of age, these mice typically develop learning and memory problems. But that didn’t happen in the absence of PirB.
Next, the researchers began thinking about how PirB might fit into the Alzheimer’s disease process, and particularly how it might interact with β-amyloid. Taeho Kim, Ph.D., a postdoctoral fellow in Dr. Shatz’s lab, theorized that since PirB resides on the surface of nerve cells, it might act as a binding site, or receptor, for β-amyloid. Indeed, he found that PirB binds tightly to β-amyloid, especially to tiny clumps of it that are believed to ultimately grow into plaques.
Although PirB is a mouse protein, humans have a closely related protein called LilrB2. The researchers found that this protein also binds tightly to β-amyloid. By examining brain tissue from people with Alzheimer’s disease, they also found evidence that LilrB2 may trigger the same harmful reactions that PirB can trigger in the mouse brain.
Considering the implications of their study, Dr. Shatz and her team concluded, “Our results show that via PirB, [soluble β-amyloid] oligomers can engage signaling pathways for neuronal actin organization that lead to synapse elimination. Therapies that selectively block LilrB2 function may be promising for treatment of Alzheimer’s disease even in the prodromal stage.”