Scientists discover potential way to repair damaged synapses in Alzheimer’s disease

While recently approved drugs for the treatment of Alzheimer’s show promise in slowing this memory-robbing disease, current treatments are far from effective in restoring memory. What’s needed are more targeted treatment options to restore memory, said Buck Institute for Research on Aging Assistant Professor Tara Tracy, Ph.D., lead author of a study that offers a strategy alternative to reverse the memory problems that accompany Alzheimer’s disease and related dementias.

Since most current research into potential treatments for Alzheimer’s disease focuses on reducing toxic proteins such as tau and beta-amyloid that accumulate in the brain as the disease progresses, the team moved away from this path to explore an alternative.

“Rather than trying to reduce toxic proteins in the brain, we are trying to reverse the damage caused by Alzheimer’s disease to restore memory,” Tracy said. The results appear in the February 1 issue of The Clinical Investigation Journal.

The work relies on a protein called KIBRA, named for its presence in the kidneys and brain. In the brain, it is mainly located at the level of synapses, which are the connections between neurons that allow the formation and recall of memories. Research has shown that KIBRA is needed at synapses to form memories, and Tracy’s team found that Alzheimer’s disease brains are deficient in KIBRA.

“We wondered how lower levels of KIBRA affected signaling at the synapse, and whether a better understanding of this mechanism could provide insight into how to repair damaged synapses during Alzheimer’s disease,” said Grant Kauwe, Ph.D, Buck scientist. ., co-first author of the study. “What we identified is a mechanism that could be targeted to repair synaptic function, and we are now trying to develop a therapy based on this work.”

The team first measured KIBRA levels in the spinal fluid of humans. They found that higher levels of KIBRA in the spinal fluid, but lower levels in the brain, correlated with the severity of dementia.

“We also discovered this amazing correlation between increased tau levels and increased KIBRA levels in the spinal fluid,” Tracy said. “It was very surprising how strong the relationship was, which really shows that the role of KIBRA is affected by tau in the brain.”

The team is exploring this phenomenon further, in the hope that KIBRA could be used as a biomarker of synaptic dysfunction and cognitive decline that could be useful for diagnosis, treatment planning and monitoring disease progression and response to treatment.

To understand how KIBRA affects synapses, the team created an abbreviated functional version of the KIBRA protein. In laboratory mice with a disease mimicking human Alzheimer’s disease, they found that this protein could reverse the memory problems associated with this type of dementia. They found that KIBRA rescues mechanisms that promote synapse resilience.

“Interestingly, KIBRA restored synaptic function and memory in mice, although it did not resolve the problem of toxic tau protein accumulation,” said Kristeen Pareja-Navarro, co-first author of the study. “Our work supports the possibility that KIBRA could be used as a therapy to improve memory after the onset of memory loss, even if the toxic protein causing the damage remains.”

Alongside other existing or future treatments, KIBRA therapy to repair synapses could be a valuable addition. “Reducing toxic proteins is of course important, but repairing synapses and improving their function is another critical factor that could help,” Tracy said. “That’s how I see it having the biggest impact in the future.”