2024 Alzheimer's Association Research Grant (AARG)
Structure and Toxicity of a Specific Tau Oligomer Related to Dementia
Can a specific variation of tau protein form clumps that hinder brain cell communication and promote early-stage dementia risk?
Peng Liu, Ph.D.
Regents of the University of Minnesota - Twin Cities
Minneapolis, MN - United States
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. In the early stages of tau accumulation, the proteins form small protein clumps called oligomers. These oligomers then continue to accumulate into tau tangles (a hallmark of many brain diseases). Studies, however, have found that tau oligomers may promote significant damage to brain cell activity well before tangles appear. For example, they may hinder the activity of synapses, the specialized structures through which brain cells transmit signals and communicate. Loss of synaptic activity can lead to memory loss and other dementia-related cognitive changes.
In preliminary studies, Dr. Peng Liu and colleagues analyzed tau content in brain tissue from people who had Alzheimer’s, MCI (a condition of subtle memory loss that may precede Alzheimer’s), or no cognitive impairment. They discovered a particular variation of tau protein (called delta tau-314) that was elevated in the Alzheimer’s brains and even more elevated in the brains with MCI. They also found that this variation may form oligomers that impact synaptic activity and brain function in the earliest stages of dementia.
Research Plan
Dr. Liu and the team will now conduct a larger study to clarify the structure and function of delta tau-314, as well as its role in Alzheimer’s disease. For their effort, they will use a novel method of isolating these tau molecules from the brain tissue of people who had Alzheimer’s or MCI. They will then examine the structural characteristics of the protein, and learn how it accumulates and how it may interact with other proteins linked to dementia. Next, they will inject delta tau-314 into nerve cells growing in laboratory dishes, in order to test whether the protein alters synaptic function in the cells. Lastly, after injecting delta tau-314 into the brains of mice with no cognitive impairment, the researchers will assess how this protein may affect the animals’ cognitive functions.
Impact
Results from Dr. Liu’s study could shed new light on how tau promotes brain cell dysfunction in the earliest stages of Alzheimer’s. It could also identify delta tau-314 as a novel target for early-stage treatments – the type of treatment that can be most beneficial for people with the disease.