Scientists have developed two new potential therapies that selectively remove aggregated tau proteins, which are associated with Alzheimer’s disease, and improve symptoms of neurodegeneration in mice.

They say this promising approach could also be applied in future to other brain disorders driven by protein aggregation inside cells, such as motor neuron disease, Huntington’s disease and Parkinson’s disease.

In two papers, published in Cell and Science, they demonstrated how utilising the unique capabilities of a protein called TRIM21 gives the potential therapies two key advantages.

Firstly, they only destroyed the disease-linked tau aggregates, leaving healthy tau proteins intact. And secondly, the therapies removed already established tau aggregates in mice, not just preventing the formation of new aggregates.

What are tau tangles?

There are two main proteins that become misfolded and accumulate into aggregates in the brains of people affected by Alzheimer’s disease: tau and amyloid.

Amyloid aggregates form in the spaces between brain cells, where they are being targeted by new antibody therapies, such as lecanemab.

In contrast, tau ‘tangles’ largely form inside nerve cells, although aggregates can spread from cell to cell, which is strongly associated with cognitive decline as the disease progresses.

It is difficult for antibody therapies to access tau inside cells, therefore they do not remove existing tau aggregates inside cells – at best they prevent aggregates from spreading.

Other techniques for targeting tau inside cells, such as anti-sense oligonucleotides (ASOs), have been shown to reduce tau in promising early-stage clinical trials. However, they act on all tau in the brain and therefore also remove ‘healthy’ tau – the long-term side-effects of this are not yet known.

‘Healthy’ tau protein normally helps to provide structural support inside nerve cells in the brain – acting as a type of scaffolding.

Dr Will McEwan, co-leader of the studies, from the UK Dementia Research Institute at the University of Cambridge said: “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. 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.”

Diana Spencer, Senior Digital Content Editor, DDW