Scientists develop selective therapy for tau tangles

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

The team of scientists from the Medical Research Council Laboratory of Molecular Biology (MRC LMB) in Cambridge, UK, and the UK Dementia Research Institute (UK DRI) at the University of Cambridge, say this promising approach could also be applied in the future to other brain disorders caused by protein aggregation in cells, such as motor neuron disease, Huntington’s disease and Parkinson’s disease.

In two articles, published in Cell And Sciencethey showed how using the unique capabilities of a protein called TRIM21 gives potential therapies two important advantages. First, they only destroyed the disease-related tau aggregates, leaving healthy tau proteins intact. And second, the therapies removed already established tau aggregates in mice, not only preventing the formation of new aggregates.

Tau tangles

There are two major proteins that misfold and build up in aggregates in the brains of people suffering from Alzheimer’s disease: tau and amyloid.

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

In contrast, tau ‘tangles’ form largely within 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 in cells, so they do not remove existing tau aggregates in cells – at best they prevent aggregates from spreading.

Other techniques for targeting tau in 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 the ‘healthy’ tau – the longer-term side effects are not yet known.

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

Trimming Alzheimer’s-linked proteins

This new technique for targeting tau tangles takes advantage of a 2010 discovery from the laboratory of Dr. Leo James of the MRC Laboratory of Molecular Biology about the role of a unique protein called TRIM21, which is a key part of the immune response on viruses.

Outside the cell, the body produces antibodies that bind to invading viruses. When the antibody-bound virus enters a cell, TRIM21 detects it and labels the virus as ‘waste’, after which it is transferred to the cell’s ‘garbage chute’, the proteasome, for destruction.

The same team, working at the UK DRI and MRC LMB, demonstrated in 2023 that TRIM21 could be repurposed to destroy tau protein aggregates associated with Alzheimer’s disease. By switching out antibodies that bind viruses to antibodies that bind to tau, TRIM21 was redirected to direct tau aggregates to be destroyed by the proteasome.

TRIM21 is particularly suitable for this because of a special property: a part of the protein called ‘RING’ that is only activated when two or more TRIM21 proteins cluster together. This means that it activates and marks its target for destruction only when TRIM21 proteins are bound to adjacent, aggregated tau proteins.

Novel Trojan horse therapy for tau aggregates

In the new studies, scientists used TRIM21 to create two new therapies that target tau aggregates.

The first therapy, ‘RING nanobody’, combines a tau-binding nanobody – a miniature version of an antibody – with the TRIM21 RING.

In the second therapeutic agent, ‘RING-Bait’, the TRIM21 RING is linked to a copy of the tau protein itself. The RING-linked tau protein acts as bait – the aggregates take it up and TRIM21 RING is also taken up. As soon as multiple RING-Baits are added to the unit, they are activated and the entire unit is destroyed.

The researchers transferred the DNA encoding the TRIM21 therapies into cells containing aggregated tau and found that it cleared the tau tangles. As hoped, the ‘healthy’ tau remained undamaged.

Dr. Will McEwan, co-leader of the studies, from the UK Dementia Research Institute at the University of Cambridge, said: “Tau aggregates are hidden away in brain cells and are very difficult to break down. Crucially, these new TRIM21-based therapies can be delivered directly into cells, where the majority of tau aggregates reside.

We have found a way that not only breaks down the tau aggregates, but leaves the healthy tau intact to do its work. The new strategy goes beyond what can be achieved with current ASO therapies being tried, as it could avoid any long-term side effects of eliminating normal tau.”

Dr. Will McEwan, UK Dementia Research Institute, University of Cambridge

Because different neurodegenerative diseases can have different types of misfolded tau, they tested the therapies on cells containing aggregated tau proteins from brain tissue donated by people with Alzheimer’s disease or progressive supranuclear palsy, which have different misfolded tau structures. The RING-Bait therapy was able to prevent tau aggregation induced by proteins from the brains of patients with both Alzheimer’s and progressive supranuclear palsy.

Dr. Leo James, co-leader of the studies, from the MRC Laboratory of Molecular Biology in Cambridge, said: “Neurodegenerative diseases can have tau proteins that misfold in many different ways, raising the possibility that each disease may require a different treatment. The useful aspect of RING-Bait is that, because it is attached to a tau protein, it is a universal Trojan horse that must be incorporated into various types of tau aggregates, just like the misfolding tau protein of the cell itself. “

Mice walk better after therapy

For the treatment to work in an animal, it must not only get to the brain, but also to the cells in the brain. To do this, the researchers used a harmless virus previously developed to deliver these types of therapies, called adeno-associated virus (AAV). It provides DNA instructions to make the modified proteins in brain cells.

Older mice with tau protein aggregates were injected with a single dose of the gene therapy vector containing either the treatment or a placebo.

Within a few weeks, there was a significant reduction in the amount of aggregated tau in the brain cells of the treated animals.

Importantly, the mice that received the RING-Bait treatment slowed the progression of their neurodegeneration symptoms and showed significantly better motor function, as assessed by an AI program that scored how well they walked.

Dr. Lauren Miller, a study author, who worked at both the UK Dementia Research Institute and the MRC Laboratory of Molecular Biology, said: “It was unknown whether specifically removing tau aggregates within the cell would be sufficient to slow the progression of the disease. to stop. It is encouraging that a RING-Bait approach reduces disease severity in our model systems, as this suggests that the selective removal of tau aggregates is a valid therapeutic approach. Further work will be needed to demonstrate that this beneficial effect is found in multiple models of human disease. “

Dr. Guido Papa, a study author from the MRC Laboratory of Molecular Biology, said: “The beauty of RING-Bait lies in its broad adaptability and potential to address other conditions characterized by the accumulation of pathological protein clusters. Other neurodegenerative diseases are caused by aggregates formed by other proteins, such as TDP43 in motor neuron diseases and alpha-synuclein in Parkinson’s disease. It is hoped that RING-Bait will enable the development of future therapies that directly target the aggregation process in these diseases.

The scientists caution that these therapies still require significant development before they can be tested in humans, particularly the development of an AAV vector that can safely and effectively deliver RING nanobody or RING bait therapies to cells in the human brain.

Dr. Jonathan Benn, a study author from the UK Dementia Research Institute at the University of Cambridge, said: “It is important to emphasize that although we have shown that it works in a mouse model, this is still a long way from being a therapeutic agent that could are applied. used in humans. It should be established that it is safe to use TRIM21-based therapies in the human brain and that the treatments are effective in clearing aggregates and improving disease progression.

“Some AAV vectors have already been approved for use in humans – for example in degenerative eye diseases and genetic diseases such as spinal muscular atrophy. However, getting enough AAV into the adult brain remains a significant challenge – the human brain is approximately 1,000 times larger than a human’s. But this is a fast-moving field and there are cutting-edge gene delivery methods that we hope will allow our therapies to be widely applied in the future.”

These studies were funded primarily by Wellcome, MRC, UK DRI and the Lister Institute of Preventative Medicine.