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Abnormal accumulations of a protein called tau can collect inside neurons, forming tangled threads and eventually harming the synaptic connection between neurons. Credit: National Institute on Aging.

New insight regarding when healthy tau proteins turn toxic in the early stages of Alzheimer’s could yield novel treatment options to utilize before the debilitating disease takes hold. 

Researchers from the UT Southwestern’s O’Donnell Brain Institute have discovered new information on the shape-shifting nature of the tau molecule prior to when it sticks to itself to form larger aggregates. They believe they have determined the precise point at which a healthy protein becomes toxic but has not yet formed deadly tangles in the brain.

“This is perhaps the biggest finding we have made to date, though it will likely be some time before any benefits materialize in the clinic,” Dr. Mark Diamond, Director for UT Southwestern's Center for Alzheimer's and Neurodegenerative Diseases, said in a statement. “This changes much of how we think about the problem.”

The new insight contradicts the long-standing belief that isolated tau proteins have no distinct shape and are only harmful after they begin to assemble with other tau proteins to form the distinct tangles seen in Alzheimer’s patient brains.

The researchers found that the tau proteins undergo a conformational change from an inert form to a pathological form in the early stages of the disease after extracting tau proteins from human brains and isolating them as single molecules.  In the inert form, there is a core region that has collapsed on itself and hides harmful amino acids.

However, in the pathological form, the tau molecule opens up and the reactive amino acids are exposed, causing it to stick to other tau proteins and enabling the formation of tangles that kill neurons.

“We think of this as the Big Bang of tau pathology,” Diamond said. “This is a way of peering to 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.”

With more than five million suffering from Alzheimer’s in the U.S., Diamond is hopeful that identifying the genesis of the disease could give scientists a target in diagnosing the condition at its earliest stage.

The researchers next plan to develop a clinical test that examines a patient’s blood or spinal fluid to detect the first biological signs of abnormal tau protein. They are also conducting studies to develop a treatment that would make the diagnosis actionable.

According to Diamond, a recently approved drug called Tafamidis stabilizes a different shape-shifting protein called transthyretin that causes deadly protein accumulation in the heart, similar to how tau overwhelms the brain.

“The hunt is on to build on this finding and make a treatment that blocks the neurodegeneration process where it begins,” Diamond said. “If it works, the incidence of Alzheimer's disease could be substantially reduced. That would be amazing.”

The study was published in eLife.

 

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