Nuclear medicine

Harnessing a probe used to image the brain in diagnosing Alzheimer’s disease and related forms of dementia; scientists at Dana-Farber Cancer Institute and Massachusetts General Hospital (MGH) have successfully cleared patient-derived brain cells of an abnormal protein associated with dementia and other neurogenerative disorders. The findings; reported in the journal eLife; provide a new tool to study the accumulation of abnormal tau protein that occurs in the brain cells of patients with Alzheimer’s and other forms of dementia; researchers say.

Neurogenerative disorders

It can help examine the effects of the rapid removal of abnormal tau from cells and may even suggest ways of preventing or reversing a build-up of the protein. “Tau has an important role in the cell: it binds to and stabilizes structures called microtubules; which give cells their shape;” says Fleur Ferguson, PhD, of Dana-Farber, co-first author of the study with M. Catarina Silva, PhD, of MGH.

“However, in neurodegenerative diseases such as Alzheimer’s; frontotemporal dementia [FTD], and progressive supranuclear palsy, abnormal tau accumulates in brain cells; which may be linked to the progression of the disease. We want to understand more about the role these aberrant proteins play in disease.”

Frontotemporal dementia

The new tool was created by taking a molecular probe used in positron emission tomography (PET) scanning for Alzheimer’s or other tau-related diseases and modifying it for a new purpose. The probe, called T807, binds specifically to the abnormal tau protein. When the probe is tagg with a radioactive isotope; therefore its binding to abnormal tau can be detected by a PET scanner, indicating the presence of disease.

To equip T807 for its new use, researchers left off the radioactive label and instead linked the compound to a molecule called an E3-ligase recruiting ligand; therefore which binds to the cell’s machinery for destroying unwanted proteins. The new, dual-action form of T807 – called QC-01-175 – grabs onto both abnormal tau and the protein-degradation machinery; bringing them close together. This proximity enables the abnormal tau to be ubiquitinat – bound to ubiquitin proteins a modification that essentially labels as cellular trash.

Therapeutic benefits

Ubiquitination sends the unwanted tau to the cell’s proteasome; where it’s breek down and eliminate. In effect; QC-01-175 becomes a device for feeding toxic tau into the cell’s trash-disposal system.When researchers tested the new tool for tau degradation in laboratory cultures of neurons derived from patients with tau mutations linked to FTD and cells from healthy volunteers; worked as designed.
It cleared away the abnormal tau from cells of patients with FTD while having minimal effect on tau in neurons from healthy volunteers. (It did show some off-target effects; interfering with a small number of proteins other than abnormal tau; but researchers have strategies for reducing such effects.) Importantly; treating FTD cells with QC-01-175 reduced their vulnerability to stress and improved their survival, indicating that degradation of abnormal tau may have therapeutic benefits.