Scientists who have recently identified the molecular start of Alzheimer's disease have used this finding to determine that it should be possible to predict which type of dementia will develop over time – a form of personalized medicine for neurodegenerative diseases.
A new study by UT Southwestern shows that single toxic tau proteins that stick together and spread degeneration in the brain of dementia patients have different forms. The creases of these molecules contain information that can help diagnose – and maybe even for one day – neurodegeneration at the earliest stages.
The intention comes from a team of scientists appointed this month in a newly established network of international collaborators aimed at improving the treatment of neurodegenerative disorders. Funded by the Chan Zuckerberg Initiative, the UT Southwestern Group is committed to using its latest Tau protein discoveries to develop clinical diagnostic tools.
"Our expanded understanding of the structure of tau proteins alters the way we think about the discovery and treatment of Alzheimer's disease and related dementia," said Dr. Mark Diamond, director of Alzheimer's Disease Center and neurodegenerative DT Southwest. "The next step is to translate this knowledge into simple clinical tests that doctors will use to diagnose and eventually stop the process of neurodegeneration at the earliest stages."
Dr. Diamond's new study expands the research published in July by his laboratory, which documents the structural "genesis" of Alzheimer's disease – the basis for how healthy tau protein changes and can then be assembled with other tau molecules to to kill brain cells.
The latest study, published in eLife indicates that the harmful single molecules tau have different forms, each of which corresponds to a separate type of larger mechanism that will be formed and self-propagating in the brain. Dr. Diamond's Laboratory has already found in a study in 2016 that the structure of larger tau aggregates determines which type of dementia will occur – which areas of the brain will be affected and how quickly the disease will spread. But it was not known what these larger structures had defined. The new study reveals how a tau molecule that changes its shape at the beginning of the disease process contains the information that defines the configuration of the larger, toxic kits. This finding suggests that the characterization of the single tau molecule conformation can predict what the initial disease is – Alzheimer's disease or other types of dementia.
Scientists have made these findings by extracting tau protein from cultured cells and human brains by isolating them as single molecules and determining what types of pathological aggregates they would produce in cells and mice. They determined that, contrary to previous ideas, a tau molecule, instead of having no structure, actually has multiple, stable structures that each determines what type of subsequent pathological assembly will be formed.
Dr. Diamond's team is trying to translate these findings into clinical tests that examine the blood of the patient or spinal fluid to detect the first biological signs of abnormal tau before the symptoms of memory loss and cognitive decline are evident. His lab also works to develop treatments to stabilize transforming molecules to prevent them from assembling or encouraging their release from the brain.
A diagnostic test will be particularly important once effective treatments for the treatment of various forms of dementia are established, he said.
"It is probably too late after the effects of neurodegeneration are manifested," said Dr. Diamond, a leading dementia expert, believing that tau acts as a prion – an infectious protein that can be reproduced independently. "We need to be able to diagnose the process early and to know the specific type of neurodegeneration that is happening because it is the best chance we need to intervene with a personalized treatment that is very analogous to how we currently use tumor genotyping, to diagnose and treat cancer most. "
Dr. Diamond heads a UT Southwestern three-member team elected by Chan Zuckerberg to join his new neurodegenerative challenge network, which brings together experimental scientists from various fields of science to understand the underlying causes of neurodegenerative disorders. The UT Southwestern Group is among the nine teams across the country that receive more than $ 1 million to continue their research.
UT Southwest Medical Center, ,