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Can increasing the levels of certain brain molecules prevent disease-related tau protein from damaging brain health?
Paul E. Fraser, Ph.D.
University of Toronto
Toronto, Canada
Background
The brain cell’s nutrient and energy transport system is organized in parallel strands like railroad tracks. These tracks allow nutrients to travel across the cell, delivering key materials throughout the cell, providing them with energy, and keeping them healthy. Tau protein normally helps keep the tracks straight. However, in Alzheimer’s and other brain diseases, the shape of tau becomes modified or “misfolded,” a change that may lead to tau accumulation, the development of tau tangles (a hallmark of these diseases), and subsequent nerve cell damage.
Proteins such as tau can be chemically modified in several ways that make the tau protein either more or less likely to clump together and form tau tangles. Recent studies have found that a chemical modification by proteins called SUMOs (small ubiquitin-like modifiers) may prevent tau accumulation. In initial research, Dr.
Paul Fraser and colleagues increased levels of a particular type of SUMO (called SUMO2) in mice genetically engineered to develop abnormal tau. They found that this treatment to increase SUMO2 prevented (1) tau-related damage to the animals’ synapses (the connections between nerve cells that promote cell-to-cell communication) and (2) impairments in their memory function. They also found lower levels of SUMO2 in the brains of individuals who had Alzheimer’s. Collectively, these findings suggest SUMO2 could be a potential target for treating tau-related brain disorders.
The researchers then began developing an improved way of administering SUMO2 into mouse brains. Their method involves delivering SUMO2 genetic material (mRNA) into the brain of the mice using an extremely small “carrier” molecule called a “nanoparticle”. This nanoparticle can be loaded with SUMO2 mRNA to carry it across the blood–brain barrier, a specialized barrier that tightly regulates what goes in and out of the brain from the circulating blood. Upon entering the brain, the SUMO2 mRNA can then be made into tau-fighting SUMO2 protein.
Research Plan
Dr. Fraser and colleagues, including Dr. Luana Fioriti, will refine and test their SUMO2 delivery method. First, they will assess how well various nanoparticles can deliver SUMO2 mRNA into nerve cells grown in a laboratory dish, and how this procedure may lead to increased SUMO2 protein levels in the cells. They will then conduct similar tests in genetically engineered Alzheimer’s-like mice to assess how well SUMO2 mRNA treatment reduces tau levels and improves memory and synapse health.
Impact
Dr. Fraser’s project could help clarify how tau accumulates in the brain during brain disease. It could also identify a novel, safe genetic therapy for preventing tau-related brain damage and memory loss in dementia.
The Tau Pipeline Enabling Program (T-PEP) is jointly funded by the Alzheimer's Association and Rainwater Charitable Foundation.
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