New research has discovered the precise point at which a healthy protein becomes toxic, offering a window into the very beginnings of Alzheimer’s disease (AD). The study, led by scientists at UT Southwestern in Dallas, TX, USA, provides novel insight into the shape-shifting nature of tau just before it begins forming large aggregates.
By extracting tau proteins from human brains and isolating them as single molecules, the researchers discovered that the harmful form of tau exposes a part of itself which is normally folded inside. This exposed portion sticks to other tau proteins, forming tangles and causing neuronal death.
“We think of this as the ‘Big Bang’ of tau pathology,” said Marc Diamond, Director for UT Southwestern’s Center for Alzheimer’s and Neurodegenerative Diseases and a leading dementia expert. “This is a way of peering [into] the very beginning of the disease process. It moves us backward to a very discreet point where we see the appearance of the first molecular change that leads to neurodegeneration in Alzheimer’s.”
Crucially, this fresh understanding offers new promise in detecting AD before its devastating memory and cognitive effects take hold. Furthermore, it could help drive new treatments to stabilise tau proteins before they shift shape. Indeed, efforts are now focused on developing blood and cerebrospinal fluid tests that can detect the first biological signs of abnormal tau proteins.
Optimism as to the potential for new therapies is also supported by the experience with tafamidis, a recently approved drug that stabilizes transthyretin, another shape-shifting protein that causes deadly protein accumulation in the heart, similar to how tau overwhelms the brain.
Overall, while still in the early stages, research in this arena could lead to a very bright future for AD. “This is perhaps the biggest finding we have made to date, though it will likely be some time before any benefits materialise in the clinic,” said Dr Diamond. “The hunt is on to build on this finding and make a treatment that blocks the neurodegeneration process where it begins. If it works, the incidence of Alzheimer’s disease could be substantially reduced. That would be amazing.”