Researchers at Indiana University School of Medicine have identified a protein that interacts with and enhances the spread of neurotoxic tau species – which is found primarily in neurons that appear abnormal in the brains of patients with Alzheimer’s disease.
The study, recently published in Natural neurosciencewas led by Cristian Lasagna-Reeves, PhD, associate professor of anatomy, cell biology, and physiology, and Pablo Martinez, PhD, postdoctoral fellow in anatomy, cell biology, and physiology and first author of the paper.
The research team found that bassoon, a presynaptic scaffolding protein, contributes to tau seed propagation and neurotoxicity. They investigated the role of bassoon on tau through mouse and Drosophila (fruit fly) models as well as human cell and human brain samples.
“The main novelty of this study is that we were the first to find the tau seed interactome, which is a species of tau that makes up less than 5% of total tau in the brain,” Lasagna-Reeves said. . “We are trying to determine the proteins that only interact with the tau seed. »
The tau seed is the species of tau that spreads through the brain, moving from neuron to neuron producing neurodegeneration, Lasagna-Reeves said. In patients with Alzheimer’s disease, the tau protein, which normally helps stabilize microtubules, is misfolded and abnormally shaped.
Previous studies on the effect of tau on neurodegeneration have identified proteins that interact with the majority of tau in the brain. Lasagna-Reeves said that by limiting their study to tau seed and the proteins it interacts with – which lead to neurotoxic events in the brain – it could lead to a more targeted approach to therapeutics for the disease. Alzheimers.
Researchers found that bassoon exacerbates tau seeding and toxicity in mouse and Drosophila models. The bassoon stabilizes the tau seed, allowing it to spread through the brain. The protein acts as a scaffold, Lasagna-Reeves said; if the bassoon is removed, it will make the tau seed more unstable. Martinez said that by lowering the level of bassoon in the models, it decreased the spread of tau, reduced brain atrophy, and improved synaptic and behavioral disorders of the disease.
“We have proven that there is a small part of tau in the brain that is very toxic in Alzheimer’s disease and other neurodegenerative diseases, and we have determined the importance of these interactions for the tau seed”, Martinez said. “The main message for the future is to target bassoon and other proteins that interact with tau seed and translate it into therapies. »
The lab is collaborating with the IU School of Medicine-Purdue Drug Discovery Center TaRget Enablement to Accelerate Therapy Development for Alzheimer’s Disease (TREAT-AD) to target bassoon with potential therapies that negatively regulate the protein in the brain.
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Materials provided by Indiana University School of Medicine. Note: Content may be edited for style and length.