Promising Novel Therapy Targets, Destroys Tau Tangles to Treat Alzheimer Disease

Researchers have developed a novel therapy that selectively removes aggregated tau proteins, which are associated with Alzheimer disease, which demonstrated success by improving neurodegeneration symptoms in mice. The findings were published in the journal Cell.

In patients with Alzheimer, there are two main proteins that become misfolded and accumulate into aggregates in the brains: tau and amyloid. Amyloid forms in the spaces between brain cells, where they are being targeted by new antibody therapies, while tau ‘tangles’ largely form inside nerve cells, and are strongly correlated with cognitive decline after disease progression. Traditionally, it has been difficult for antibody therapies to access tau inside cells, therefore they do not remove existing tau aggregates inside cells.

This new technique for targeting tau tangles utilizes a previous a discovery regarding the role of a unique protein called TRIM21, which is a key part of the immune response to viruses. The investigators used TRIM21 to create two new therapies to target tau aggregates. The first therapy, called ‘RING-nanobody’, combines a tau-binding nanobody with the TRIM21 RING.

The second therapeutic, called ‘RING-Bait’, has the TRIM21 RING joined to a copy of the tau protein itself. The RING-linked  tau protein therapy acts as bait – the aggregates incorporate it and TRIM21 RING gets incorporated as well. Once multiple RING-Baits are added to the aggregate, they become activated and causes the entire aggregate to be destroyed, the researchers noted.

The researchers showed that DNA encoding the TRIM21 therapies into cells containing aggregated tau cleared the tau tangles. As hoped, ‘healthy’ tau was left undamaged. Dr Will McEwan, co-leader of the studies, from the UK Dementia Research Institute at the University of Cambridge said via a press release: “Tau aggregates are tucked away inside brain cells and very difficult to degrade. Critically, these new TRIM21-based therapies can be delivered directly inside cells, where the majority of tau aggregates reside.

“We’ve found a way that not only degrades the tau aggregates, but leaves the healthy tau intact to do its job. The new strategy goes beyond what can be achieved with current ASO therapies that are being trialled, as it could avoid any potential long-term side-effects of eliminating normal tau.”