Scientists have created promising new treatments that can specifically eliminate aggregated tau proteins linked to Alzheimer’s disease and alleviate neurodegeneration symptoms in mice.
Researchers have crafted innovative potential therapies aimed at selectively removing tau protein aggregates associated with Alzheimer’s, leading to improved neurodegeneration symptoms in mouse models.
A research team from the Medical Research Council Laboratory of Molecular Biology (MRC LMB) in Cambridge, UK, along with the UK Dementia Research Institute (UK DRI) at the University of Cambridge, believe this effective strategy could eventually be applied to other brain disorders caused by protein accumulation within cells, such as motor neuron disease, Huntington’s disease, and Parkinson’s disease.
In two studies published in Cell and Science, the researchers detailed how leveraging the unique properties of a protein named TRIM21 provides their potential therapies with two significant benefits: they specifically dismantle the tau aggregates linked to the disease while sparing healthy tau proteins, and they also eliminate existing tau aggregates in mice rather than merely preventing new ones from forming.
Tau tangles
In Alzheimer’s-affected brains, two main proteins misfold and cluster into aggregates: tau and amyloid.
Amyloid aggregates accumulate in the spaces between brain cells, where they are targeted by new antibody treatments, including lecanemab.
Conversely, tau ‘tangles’ primarily develop inside neurons, but can spread between cells, significantly correlating with cognitive decline as the disease progresses.
Antibody therapies struggle to access tau within cells, meaning they do not eliminate existing tau aggregates. At best, they stop the spread of aggregates.
Other methods that target tau in cells, such as anti-sense oligonucleotides (ASOs), have shown promise in early clinical trials by reducing tau levels. However, these methods indiscriminately affect all tau in the brain, including ‘healthy’ tau—the long-term consequences of this approach are still unknown.
‘Healthy’ tau is crucial for providing structural support within neurons, functioning like scaffolding.
Trimming Alzheimer’s-linked proteins
The innovative approach to targeting tau tangles builds on a 2010 discovery by Dr. Leo James’ lab at the MRC LMB about the role of the special protein TRIM21, which plays a key part in the immune response to viruses.
When viruses invade the body, antibodies are produced to attach to them. Once an antibody-bound virus enters a cell, TRIM21 identifies it and marks it as ‘waste,’ ushering it into the cell’s waste disposal system, the proteasome, for degradation.
In 2023, the same team showcased that TRIM21 could be repurposed to destroy tau protein aggregates tied to Alzheimer’s disease. By replacing the antibodies that bind to viruses with those binding to tau, TRIM21 was redirected to mark tau aggregates for destruction by the proteasome.
TRIM21 is particularly efficient in this due to a unique feature, a component called ‘RING,’ which activates only when two or more TRIM21 proteins cluster together. This activation ensures it only targets aggregates when TRIM21 proteins are attached to neighboring tau aggregates.
New Trojan horse therapy for tau aggregates
In their recent studies, scientists developed two new therapies using TRIM21 to target tau aggregates.
The first therapy, named ‘RING-nanobody,’ combines a tau-binding nanobody—a miniature antibody—with the TRIM21 RING.
The second treatment, ‘RING-Bait,’ connects the TRIM21 RING to a tau protein duplicate. This RING-linked tau protein serves as bait, leading aggregates to incorporate it along with the TRIM21 RING. Once several RING-Baits attach to an aggregate, they become activated, triggering the destruction of the entire aggregate.
The team introduced the DNA encoding these TRIM21 therapies into cells with aggregated tau and successfully cleared the tau tangles, leaving ‘healthy’ tau unharmed.
Dr. Will McEwan, co-leader of the studies at the UK Dementia Research Institute, stated: “Tau aggregates are hidden within brain cells and are notoriously hard to eliminate. Notably, these new TRIM21-based therapies can be delivered directly into the cells where most tau aggregates exist. We’ve developed a method that not only removes tau aggregates but also preserves healthy tau for its essential functions. This strategy surpasses the capabilities of current ASO therapies that are under investigation, potentially avoiding adverse long-term effects of removing normal tau.”
Given that various neurodegenerative conditions have different forms of misfolded tau, the research team tested the therapies on cells containing aggregated tau proteins from brain tissue donated by individuals with Alzheimer’s and progressive supranuclear palsy, both exhibiting diverse tau misfolding structures. The RING-Bait therapy successfully hindered tau aggregation induced by proteins from both Alzheimer’s and progressive supranuclear palsy brain samples.
Dr. Leo James, co-leader of the studies, remarked: “Neurodegenerative diseases manifest with tau proteins misfolding in numerous ways, leading to the necessity for tailored treatments for each condition. An advantageous aspect of RING-Bait is its attachment to tau protein, rendering it a universal Trojan horse that should seamlessly integrate into various tau aggregates just like the cell’s misfolded tau.”
Mice show improvement after therapy
For effective treatment in animals, it is crucial that the therapy penetrates the brain and gets inside brain cells. To achieve this, the researchers utilized a harmless adeno-associated virus (AAV) previously developed for delivering such therapies. This virus transmits DNA instructions for creating the custom proteins within brain cells.
Older mice with aggregated tau received a single injection of the gene therapy vector containing either the treatment or a placebo.
Within weeks, there was a notable decrease in aggregated tau levels in the brains of the treated mice.
Importantly, the mice receiving the RING-Bait treatment experienced a slowdown in their neurodegeneration symptoms and exhibited significantly improved motor abilities, as measured by an AI program assessing their running performance.
Dr. Lauren Miller, a co-author of the study from both the UK Dementia Research Institute and MRC Laboratory of Molecular Biology, explained: “It was previously uncertain whether the targeted removal of tau aggregates within cells would be sufficient to stop disease progression. It’s promising that the RING-Bait method shows a reduction in disease severity in our model systems, suggesting that selectively removing tau aggregates is a valid therapeutic strategy. More research is necessary to confirm this positive effect across various human disease models.”
Dr. Guido Papa, another study author from the MRC Laboratory of Molecular Biology, added: “The beauty of the RING-Bait approach lies in its broad applicability, allowing for the potential treatment of other diseases characterized by pathological protein aggregates. Other neurodegenerative diseases involve aggregates made up of different proteins, such as TDP43 in motor neuron disease and alpha-synuclein in Parkinson’s disease. We hope that RING-Bait will facilitate the development of future therapies targeting the aggregation process in these diseases.”
The researchers caution that these new therapies require further development before being tested on humans, particularly the creation of an AAV vector that can safely and efficiently deliver RING-nanobody or RING-Bait therapies to cells throughout the human brain.
Dr. Jonathan Benn, a study author from the UK Dementia Research Institute at the University of Cambridge, emphasized: “It’s critical to underline that while we have demonstrated success in a mouse model, we are still far from having a treatment suitable for humans. It is essential to assess the safety of using TRIM21-based therapies in the human brain and to ensure the treatments effectively remove aggregates while improving disease progression.”
Currently, some AAV vectors have been approved for human use, such as those for treating degenerative eye diseases and genetic disorders like spinal muscular atrophy. However, ensuring sufficient AAV delivery to the adult brain remains a significant challenge, as the human brain’s size is about 1,000 times larger than that of a mouse. Nevertheless, this area is advancing rapidly, and novel gene delivery methods are being explored that may enable large-scale delivery of these therapies in the future.
This research was primarily supported by Wellcome, MRC, UK DRI, and The Lister Institute of Preventative Medicine.
