by Cristina Marrone
Research in a very preliminary phase, for now on mice, indicates the way to repair the synapses between neurons with the aim of restoring memories to Alzheimer’s patients. The deficient protein in diseased brains
Is it possible to find a way to cure Alzheimer’s disease by reversing memory problems? To do this it would be necessary to repair the damaged synapses, restoring the dialogue between the neurons affected by the neurodegenerative pathology which represents the first form of dementia in the world, with numbers of at least 600 thousand patients in Italy alone. In the United States, scientists from the Buck Institute for Research on Aging with colleagues from the University of California and New York have chosen to follow this path: by immersing themselves in the complexities of the human brain, scientists have collected new evidence on a promising alternative strategy that revolves around the protein Kibrafound to be deficient in the brains of individuals affected by Alzheimer’s.
The study, published in the Journal of Clinical Investigation, currently conducted on mice, focuses on the vital role that Kibra plays in the formation of memory and in the function of synapses, fundamental for the construction of memory. The research team discovered that Kibra is necessary for synapses to form memories.
Research on amyloid plaques and tau
Today, most of the ongoing projects to identify possible anti-Alzheimer’s treatments focus on reducing the accumulation of toxic proteins (tau and beta-amyloid) in the brain, in order to slow the progression of the disease. Some monoclonal drugs such as Lecanemab, Aducanumab, Donanemab which target amyloid have already been approved by the American FDA and are currently in use in the United States, although the therapies are still controversial, since the biological benefits (the reduction of beta amyloid and tau plaques) do not yet translate into clinical benefits (i.e. with concrete and tangible effects on patients), while the side effects of these monoclonals can be important.
Restore memory
The working group led by Tara Tracy, a geriatrician who has been working on these issues for some time, while supporting the importance of eliminating or reducing the toxic proteins linked to Alzheimer’s disease, the underlying problem of the disease, wanted to investigate how to restore the memories, seeking tangible solutions for patients. We are trying to reverse the brain damage caused by Alzheimer’s to restore memory, explains Tracy, senior author of the study.
What Kibra
His team focused on a protein called Kibra because it is found in the kidney and brain. At the brain level, Kibra is mainly located in the synapses. Research has shown that Kibra is essential for synapses to build a memory, and scientists have found that this protein is deficient in Alzheimer’s brains. We asked ourselves how lower levels of Kibra affected the exchange of signals within synapses, says Grant Kauwe, co-first author of the work. We have identified a mechanism that could be used to repair synaptic function – he underlines – and now, on this basis, we are trying to develop a therapy.
Biomarcatore
First the American scientists measured concentrations of Kibra in human cerebrospinal fluid, observing that higher levels of this protein in the cerebrospinal fluid and lower levels in the brain were linked to the severity of dementia. Not only that: We also discovered a surprising correlation between the increase in tau levels and the increase in Kibra levels in the cerebrospinal fluid, underlines Tracy. A surprisingly strong relationship – precise – that proves Kibra’s role in influencing tau in the brain. A fact that researchers are investigating, in the hope that Kibra can be used as a biomarker of synaptic dysfunction and cognitive decline, useful for diagnosis, treatment planning and monitoring of Alzheimer’s progression and response to therapy.
The restoration of synapses (but the accumulation of tau protein remains)
Subsequently, to understand how Kibra affects synapses, the American team created a functionally reduced version of the protein and tested it on laboratory mice with a disease that mimics human Alzheimer’s. It turns out that Kibra can reverse the memory deterioration associated with this type of dementia, because it saves the mechanisms that promote the resilience of the synapses. For Kristeen Pareja-Navarro, co-first author of the study, it is interesting to note that Kibra restored synaptic function and memory in mice with dementia, although it did not solve the problem of the accumulation of toxic tau protein. Our work – says Pareja-Navarro – supports the possibility that Kibra can be used as a therapy to improve memory after the onset of its deterioration, even if the toxic protein, beta amyloid or tau, at the origin of the damage remains.
Future prospects
While more research is needed to fully understand the complexities of Kibra and its therapeutic potential, these initial results are encouraging and pave the way for more targeted and effective treatments for Alzheimer’s disease. It should be underlined, however, that the research is still in the pre-clinical phase, and even if the data seem promising it takes time to arrive at possible human trials and, unfortunately, we don’t always get there. However, together with other treatments already developed or that will arrive in the future, a therapy with Kibra to repair synapses could be valuable, the authors underline.
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February 2, 2024 (modified February 2, 2024 | 6:02 pm)
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