Scientists at the Buck Institute for Research on Aging, the University of California, San Francisco, and elsewhere have proposed a strategy for repairing damaged synapses in Alzheimer’s disease and related dementias in mice. Details of the study in mouse models are available in The Journal of Clinical Investigation in a paper titled “KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss.”
Current research into potential treatments for Alzheimer’s disease focus on preventing the accumulation of toxic proteins like tau and amyloid beta in the brain, which impact memory as the disease progresses. For this study, the researchers focused on methods of reversing the damage to the synapses to restore memory. The work hinges on a postsynaptic protein called KIBRA which is encoded by WWC1, a gene linked to memory and risk of late-onset Alzheimer’s diseases in humans.
KIBRA is found in the kidneys and the brain where it is localized at the synapses. The scientists showed that levels of this protein, which is required for synapses to form memories, are lower in brains with Alzheimer’s disease. Furthermore, they found that higher levels of KIBRA in cerebrospinal fluid and lower levels in the brain corresponded to the severity of dementia. “We also found this amazing correlation between increased tau levels and increased KIBRA levels in the cerebrospinal fluid,” said Tara Tracy, PhD, an assistant professor at Buck and the study’s senior author. “It was very surprising how strong the relationship was, which really points to the role of KIBRA being affected by tau in the brain.”
The team also dug into how KIBRA affects synapse signaling. Specifically, “we wondered how the lower levels of KIBRA affected signaling at the synapse, and whether understanding that mechanism better could yield some insight into how to repair the synapses damaged during the course of Alzheimer’s disease,” said Grant Kauwe, PhD, a staff scientist at Buck and co-first author of the study.
To answer that question, they created a shortened functional version of the KIBRA protein and tested it in transgenic mice with a condition that mimics Alzheimer’s disease. The results showed that KIBRA reversed the memory impairment associated with this type of dementia and rescued mechanisms that promote synapse resilience. “Interestingly, KIBRA restored synaptic function and memory in mice, despite not fixing the problem of toxic tau protein accumulation,” said Kristeen Pareja-Navarro, PhD, a Buck research scientist and a 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 though the toxic protein that caused the damage remains.”
With further study, the KIBRA protein could potentially be used as a biomarker of synaptic dysfunction and cognitive decline which could help with Alzheimer’s disease diagnosis and progression, treatment planning, and treatment response. A KIBRA-based therapy could also work alongside other therapies that prevent pathologic protein accumulation in the brain. “Reducing toxic proteins is of course important, but repairing synapses and improving their function is another critical factor that could help,” Tracy noted. “That’s how I see this making the biggest impact in the future.”