The changes in the tau protein are related to the dementia stage of Alzheimer’s disease

Alzheimer’s disease research has long focused on understanding the role of two key proteins, beta amyloid and the tau protein. Found in tangles in the brain tissue of patients, a pathological form of the tau protein contributes to the spread of the disease in the brain.

In new research from their joint lab, Judith Steen, Ph.D., and Hanno Steen, Ph.D. show for the first time that this pathological tau protein changes its shapes over time, which could mean it will take longer. drugs to target it effectively.

For years, pharmaceutical companies have largely focused with very limited success on developing Alzheimer’s drugs against beta amyloid. More recently, drug discovery has shifted to tau drugs. This new tau discovery may help prevent the same fate as the drugs currently under development against tau because it shows that the protein can present itself with a number of targets in the early stages, with other targets later in the disease process.

“The tau protein in Alzheimer’s disease looks different at each stage,” says researcher Judith Steen. “We found that tau undergoes a series of chemical changes in a gradual process related to disease severity. This suggests that we need different diagnoses and treatments for each stage of the disease.”

Published in an article in Cell, this research represents years of work in the Steen laboratory funded by the Tau Consortium. Its mission is to accelerate the discovery of new treatments for Alzheimer’s and other diseases related to “tauopathies”, abnormalities of the tau protein.

Tau changes with the stage of dementia

The Steen lab team examined tau aggregates in the tissues of two areas of the human brain, the frontal gyrus and the angular gyrus, from 49 patients with AD and 42 individuals of the same age with no known Alzheimer’s or dementia. They found that the chemistry of the tau protein changed in Alzheimer’s patients. Tau had several modifications not found on normal tau, known as post-translational chemical modifications or PTMs. Specific forms of chemically modified tau were related to the stage of dementia.

Gradual chemical changes

As we age, tangles of tau build up in our brains, even if we don’t develop dementia. “But these aggregates aren’t as abundant and don’t look like tau aggregates in patients who have severe Alzheimer’s disease,” says Steen. He believes that tau undergoes chemical changes after it is first produced in the body. Their team revealed 95 PTMs of the tau protein; about a third of them have not been described before.

“Chemical treatment by a variety of enzymes introduces modifications to the original tau protein,” says Steen. Examples included the addition of phosphate, methyl, acetyl and ubiquitin groups and others. The first step of the disease appears to begin with the addition of phosphate, with other changes following in a gradual process. “We were able to see exactly what these changes were, the extent of the changes, and we could also map it to a precise area of ​​the tau protein,” says Steen.

More than one drug is probably needed

The team’s discovery has immediate implications for the future of Alzheimer’s treatment.

“It is likely that to successfully target tau with an antibody or small molecule, it may take more than one to eliminate it,” says Steen. “Early intervention may require different therapies than late-stage Alzheimer’s because of the distinct PTM profiles associated with each stage of the disease.”

The team hopes that exploring some of these crucial chemical modifications will help explain how Alzheimer’s develops and progresses, as well as further reveal the chemistry of the tau protein in its early stages.

FLEXITau technology platform

The key to the study was the use of a new mass spectrometry technique developed in-house to measure proteins. Called FLEXITau and first described in an article in 2016, it can sequence and quantify the makeup of tau with unprecedented accuracy. FLEXITau uses biochemistry, mass spectrometry and data analysis to provide information on the chemical changes of tau in brain tissue.

The Steen lab leveraged the platform to study brain tissues collected from NIH-funded brain banks from patients with neurodegenerative diseases, using it to analyze thousands of proteins from these tissues.

The FLEXITau approach provides a deeper understanding of the tau pathology that the team believes may lead to new therapies. It may also be useful for developing better diagnostic tools for identifying biomarkers of Alzheimer’s and other tau-associated diseases.