Stanford Bio-X Researchers’ “Decoy Drug” Could Someday Do Wonders For Alzheimer’s Disease

A recent study revealed the mechanism to restore the capability of neurons to form new synapses, entitled, “Blocking PirB up-regulates spines and functional synapses to unlock visual cortical plasticity and facilitate recovery from amblyopia,” which was published in Science Translational Medicine by David Bochner and Richard W. Sapp, first co-authors from the work, part of the group of Dr. Carla Shatz, from the Department of Biology and Bio-X, Stanford University, CA, U.S.A. the findings of the study suggest that the newfound capability may have the potential to be applied to clinical conditions such as stroke, forms of blindness, or Alzheimer’s disease.

During brain development, the neurons respond to various stimuli by forming new synapses, although this capacity decreases substantially in adults. Dr. Shatz and collaborators described previously a protein called Paired-immunoglobulin-like receptor B (PirB), a major histocompatibility complex class I (MHCI) receptor, localized in mice on the surface of neurons and immune cells. The PirB protein seems to control the time “window” for synapse formation. When there is no stimulation of PirB, the neurons are able to form new synapses. But when there is stimulation, other proteins latch onto PirB and the “window” is closed — a process that occurs mostly during adult life — and there is inhibition of synapse formation. PirB is essentially an on/off switch system for synapse formation. Therefore, the million dollar question has been what controls that “window” and how can we open it during adulthood and mainly during disabling conditions such as stroke, some forms of blindness, Alzheimer’s disease and other neurodegenerative conditions.

“To me, this is amazing because what this is saying is that it is possible to induce new synapses in adult brains,” said Dr. Carla Shatz, David Starr Jordan Director of Stanford Bio-X, in the Stanford press release.

In previous work, the researchers used mice deficient for PirB and showed that the “window” for synapses formation was closed during adult life. These mice recovered faster from stroke and could create synapses in their visual systems also when adults. This work opened a series of interesting questions, mainly, if these findings could be translated to humans, although this exact type of experimental approach is impossible to achieve in humans.

David Bochner and Richard W. Sapp engineered a form of PirB that functions like a trap for proteins that would bind the PirB and, consequently, inhibit synapse formation. The use of the trap would leave the intrinsic PirB vacant and silent, turning the synapse formation process to the “on” position. The researchers tested the trap PirB in an animal model of blindness, which has the inability to create new synapses in the adult visual system. The treated adult mice were able to form new synapses and recover some vision. They quantified the physical connections that existed in the visual system, and significantly more were found in the mice that had received the trap PirB.

“If the damage isn’t repaired early enough, then it’s extremely difficult if not impossible to recover vision,” said Dr. Shatz.

“Wouldn’t it be great if while you were in rehabilitation after stroke you could open the plasticity just briefly, then close it again to allow recovery of speech?” questioned Dr. Shatz.

“It seems reasonable to suggest taking daily doses of drug that might keep the synapse formation ‘window’ open permanently. At first I thought, ‘I want to take this pill right away,’ but maybe we want to think about that,” said Dr. Shatz.

“During these early critical periods you want to learn rapidly,” said Dr. Shatz, who is also the Sapp Family Provostial Professor and professor of biology and of neurobiology at Stanford University School of Medicine. “When this is happening, the connections are changing so fast that they are very unstable. This is part of why kids are susceptible to epilepsy. After the critical period you want to stabilize and avoid the risk of deleting connections that you really need,” added Dr. Shatz.

There are still some difficulties to be overcome in developing such a trap to be used in humans: first the researchers need to assessed if the human homologue of PirB will produce similar findings as the ones of the mouse counterpart; second, in this work, sPirB was delivered directly into the mouse brain because this drug does not cross the blood-brain barrier, the physiological barrier that prevents potential toxins passing from the systemic circulation to the brain.

“The good news is that the adult brain houses some of the molecules and mechanisms needed to create robust new connections, but normally these mechanisms are mostly turned off,” said Dr. Shatz. “The decoy PirB shows that they are accessible under the right circumstances,” added Dr. Shatz.