Caption: The protein tau (green) aggregates abnormally in a brain cell (blue). Tau spills out of the cell and enters the bloodstream (red). Research shows that antibodies (blue) can capture tau in the blood that reflect its levels in the brain. Credit: Sara Moser
Age can bring moments of forgetfulness. It can also bring concern that the forgetfulness might be a sign of early Alzheimer’s disease. For those who decide to have it checked out, doctors are likely to administer brief memory exams to assess the situation, and medical tests to search for causes of memory loss. Brain imaging and spinal taps can also help to look for signs of the disease. But an absolutely definitive diagnosis of Alzheimer’s disease is only possible today by examining a person’s brain postmortem. A need exists for a simple, less-invasive test to diagnose Alzheimer’s disease and similar neurodegenerative conditions in living people, perhaps even before memory loss becomes obvious.
One answer may lie in a protein called tau, which accumulates in abnormal tangles in the brains of people with Alzheimer’s disease and other “tauopathy” disorders. In recent years, researchers have been busy designing an antibody to target tau in hopes that this immunotherapy approach might slow or even reverse Alzheimer’s devastating symptoms, with promising early results in mice [1, 2]. Now, an NIH-funded research team that developed one such antibody have found it might also open the door to a simple blood test .
Caption: PET scan images show distribution of tau (top panel) and beta-amyloid (bottom panel) across a brain with early Alzheimer’s disease. Red indicates highest levels of protein binding, dark blue the lowest, yellows and oranges indicate moderate binding. Credit: Brier et al., Sci Transl Med
In people with Alzheimer’s disease, changes in the brain begin many years before the first sign of memory problems. Those changes include the gradual accumulation of beta-amyloid peptides and tau proteins, which form plaques and tangles that are considered hallmarks of the disease. While amyloid plaques have received much attention as an early indicator of disease, until very recently there hadn’t been any way during life to measure the buildup of tau protein in the brain. As a result, much less is known about the timing and distribution of tau tangles and its relationship to memory loss.
Now, in a study published in Science Translational Medicine, an NIH-supported research team has produced some of the first maps showing where tau proteins build up in the brains of people with early Alzheimer’s disease . The new findings suggest that while beta-amyloid remains a reliable early sign of Alzheimer’s disease, tau may be a more informative predictor of a person’s cognitive decline and potential response to treatment.
Caption: Left to right, brain PET scans of healthy control; former NFL player with suspected chronic traumatic encephalopathy (CTE); and person with Alzheimer’s disease (AD). Areas with highest levels of abnormal tau protein appear red/yellow; medium, green; and lowest, blue. Credit: Adapted from Barrio et al., PNAS
If you follow the National Football League (NFL), you may have heard some former players describe their struggles with a type of traumatic brain injury called chronic traumatic encephalopathy (CTE). Known to be associated with repeated, hard blows to the head, this neurodegenerative disorder can diminish the ability to think critically, slow motor skills, and lead to volatile, even suicidal, mood swings. What’s doubly frustrating to both patients and physicians is that CTE has only been possible to diagnose conclusively after death (via autopsy) because it’s indistinguishable from many other brain conditions with current imaging methods.
But help might be starting to move out of the backfield toward the goal line of more accurate diagnosis. In findings published in the journal PNAS , NIH-supported scientists from the University of California, Los Angeles (UCLA) and the University of Chicago report they’ve made some progress toward imaging CTE in living people. Following up on their preliminary work published in 2013 , the researchers used a specially developed radioactive tracer that lights up a neural protein, called tau, known to deposit in certain areas of the brain in individuals with CTE. They used this approach on PET scans of the brains of 14 former NFL players suspected of having CTE, generating maps of tau distribution throughout various regions of the brain.
Caption: A plaque (orange) disrupts the normal network of human neurons (green) grown in a three-dimensional gel in the lab, mimicking the brain anatomy of Alzheimer’s patients. Credit: Doo Yeon Kim and Rudolph E. Tanzi, Massachusetts General Hospital/ Harvard Medical School
Researchers want desperately to develop treatments to help the more than 5 million Americans with Alzheimer’s disease and the millions more at risk. But that’s proven to be extremely challenging for a variety of reasons, including the fact that it’s been extraordinarily difficult to mimic the brain’s complexity in standard laboratory models. So, that’s why I was particularly excited by the recent news that an NIH-supported team, led by Rudolph Tanzi at Boston’s Massachusetts General Hospital, has developed a new model called “Alzheimer’s in a dish.”
So, how did Tanzi’s group succeed where others have run up against a brick wall? The answer appears to lie in their decision to add a third dimension to their disease model. Previous attempts at growing human brain cells in the lab and inducing them to form the plaques and tangles characteristic of Alzheimer’s disease were performed in a two-dimensional Petri dish system. And, in this flat, 2-D environment, plaques and tangles simply didn’t appear.