Brain Protein Tau Gets New Focus in AD Research
A novel scanning technique is being hailed as a major advance in Alzheimer’s disease (AD) research. A team of scientists led by neurologist Keith Johnson, MD, head of the Massachusetts General Hospital (MGH) Clinical Brain Positron Emission Tomography (PET) Service, is among the first to test a new imaging compound that helps detect in healthy adults the buildup within the brain of an abnormal form of the protein tau, which is one of the two major hallmarks of AD. The technique, which allows detection of tau accumulation before any symptoms of the neuro-degenerative disease are apparent, has heightened interest in tau among researchers.
“We are starting to learn more about tau’s role in part because of this new tau imaging process that Dr. Johnson is bringing to the MGH research community,” says Deborah Black-er, MD, ScD, Director of the Gerontology Research Unit at MGH and Associate Vice Chair for Re-search in MGH Psychiatry. “We can now see tau in living individuals and observe how it interacts with abnormal forms of beta-amyloid, another protein that is associated with AD development. The improved ability to visualize tau should help us significantly in developing a better understanding of how the disease unfolds, and may help in the development of potential AD treatments.”
Complex interaction
Initially, Alzheimer’s research focused heavily on sticky clusters of beta-amyloid plaques that cluttered the spaces between neurons as a primary causative factor of AD. The impact of the twisted fibrils of abnormal tau was less clear, and efforts to develop treatments for AD focused largely on amyloid.
However, trials of experimental compounds designed to eliminate amyloid plaque have been disappointing. Scientists have found that even when these drugs managed to reduce brain plaque, the AD process still continued. At the same time, researchers have developed new insights into the role of tau in AD.
“More recent research on tau has not supplanted the amyloid theory of AD, but it has contributed to a more complex model of the disease,” explains Dr. Blacker. “We need to be open to broader views of the disease process as new findings emerge in our efforts to under-stand this disease.”
WHAT YOU CAN DO
The best protection against developing tau pathologies consists of following a brain-healthy life-style, which includes:
- Getting plenty of sleep. Seven to eight hours a night is recommended.
- Engaging in regular exercise—at least 30 minutes a day, five days a week.
- Lowering stress levels as much as possible, and engaging in relaxation techniques to counter the effects of stress.
- Consuming a nutritious, low-calorie diet with plenty of fresh fruits and vegetables, legumes, nuts, lean meats, low-fat dairy products and healthy fats, such as canola and olive oils.
- Consumption of omega-3 fatty acids found in fish and fish oil has long been associated with positive effects on brain health, and although very preliminary, some research suggests that con-sumption of caffeinated coffee may help protect the brain against tau pathologies.
Linked to decline
Normally, tau proteins bind to hollow rods called microtubules within the axons and dendrites of nerve cells. Healthy tau proteins support the structure of the microtubules, which act as coduits along which nutrients and proteins move and toxins are eliminated from the cell. However, in AD tau proteins detach from the microtubules and aggregate to one another, forming twisted strands known as neurofibrillary tangles. This transformation eventually impedes the action of the microtubules and leads to cell death.
In work with animal models for AD and post-mortem studies of humans with the disease, scientists have learned that abnormal changes in tau are closely associated with a decline in cognition. In contrast, the burden of amyloid plaques does not appear to correlate well with cognitive changes. There is also some evidence that damage associated with both tau and amyloid may be harmful at earlier stages in the disease process, even before they coalesce to form plaques or tangles.
Learning about Tau
A recent MGH study, which Dr. Johnson and his colleagues presented at the 2014 Alzheimer’s Association International Conference, involved taking PET scans of the brains of 56 cognitively normal older adults using a newly developed imaging compound that binds to tau. The researchers compared the results of the scans with the memory performance of the participants, who had undergone annual memory testing during the previous three years. Results showed a strong correlation between an increasing buildup of abnormal tau in certain cortical regions of partici-pants’ brains and declining scores on memory tests over time. The researchers believe their findings suggest that the spread of tau, under the influence of, or in the presence of beta-amyloid, may be a sign that cognitive decline is imminent or already underway. The ability to detect these changes before symptoms emerge is very important for an understanding of the AD process and for the development of early intervention strategies and therapies.
The MGH research is one of several recent studies attempting to shed light on the role of tau in AD. Another, an animal study published in the Oct. 31, 2014 issue of Molecular Neurodegen-eration, suggests that AD may be triggered when abnormal tau proteins lose their ability to help in the process of clearing beta-amyloid from brain cells. The study authors theorized that mal-functioning tau leads to a build-up of amyloid within brain cells accompanied by a spillover of amy-loid plaque into the spaces between brain cells, and that cell death results from excess levels of am-yloid inside the cells, rather than the sticky plaques outside them. They suggest that finding drugs to restore normal tau functioning might clear amyloid buildup from the cell, reduce plaque formation, and prevent cell death, halting AD progression.
A review published in the May 21, 2014 issue of Neuron suggests that the accumulation of abnormal forms of both tau and amyloid in the brain’s synapses (communication points between brain cells) may cause them to degenerate, and thus lead to the declines in cognition characteristic of AD. The authors theorized that abnormal tau may spread beyond the local region through the brain’s synaptic system, spreading harm throughout the brain’s circuits as neurodegeneration progresses.
Efforts to find therapies that would halt or reverse abnormal changes in tau are ongoing. Scientists are working on vaccines that have shown promise in reducing tau aggregation and neurofibrillary pathologies in animals, and testing several promising anti-tau drug compounds, some of which have shown success in animal models. One such compound, the cancer drug nilotinib, appears to stimulate tau to promote the removal of beta-amyloid from within the cell and is already scheduled for clinical trials in humans.
“The growing knowledge about the biology of tau, its effects on brain health, and its relationship with beta-amyloid is part of ongoing, incremental progress that is deepening our understanding of AD,” says Dr. Blacker. “This work will continue as we develop a more complete model of the disease process, setting the stage for new pharmacological agents.”
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