Novel Trojan Horse Therapy Specifically Degrades Tau Protein

Alzheimer's disease (AD) belongs to a group of neurodegenerative diseases that severely affect brain thinking, cognitive and memory functions, and impose far-reaching and serious burdens on families and society. It is well known that there are two misfolded and aggregated proteins in the neurons of the brain of AD patients: β-amyloid (Aβ) and Tau proteins. These two protein aggregates are diagnostic markers for AD patients and are also considered to be key drivers of AD development, thus targeting and removing these proteins is an important strategy in the development of AD therapies.

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In this article, Creative Biolabs introduces novel therapies that are specific for removing disease-associated Tau protein aggregates and blocking aggregate formation, exploring the mysteries of precision therapy for AD.

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Targeted Clearance of Protein Aggregation: Explorations and Bottlenecks

Antibody therapies for Aβ, which form in the spaces between brain cells, have shown initial success. two monoclonal antibodies for early Alzheimer's disease were approved by the FDA in 2023 and July 2024: Lecanemab and Donanemab, which target Aβ. Monoclonal antibodies are able to reduce amyloid β plaques in the brain, thereby slowing cognitive decline in patients by 25 to 35 percent. Monoclonal antibodies reduce amyloid β plaques in the brain, which in turn slows cognitive decline by 25 to 35 percent. Although drugs cannot cure AD, they can slow the disease process and improve quality of life.

Targeted removal of Tau protein aggregates is challenging. One of the hallmark pathologies of AD is neurofibrillary tangles composed of highly phosphorylated Tau protein (P-Tau), which are mainly formed inside nerve cells and are difficult for therapeutic antibodies to access. Other strategies for targeting intracellular Tau, such as antisense oligonucleotides (ASOs), have been effective in reducing intracellular Tau in early clinical trials, but they act on all Tau proteins in the brain, removing healthy Tau. How to specifically remove phosphorylated Tau aggregates is key.

Creative Biolabs is a key supplier of neuroscience research tools worldwide, specializing in the research, development and production of high quality neural cells, antibody products. For Tau protein related research, we offer a range of research tools, including but not limited to the following:

Novel Trojan Horse Therapy: Specific Clearance of Tau Protein Tangles

Recently, researchers published articles developing two new therapies for AD that utilize the TRIM21 protein to precisely remove Tau protein aggregates.

• TRIM21 as a tool for capturing Tau aggregates

The new technologies published targeting Tau aggregates all utilize the TRIM21 protein, which was initially shown to play an important role in the immune system's response to viral invasion. When a virus invades the body, antibodies produced by the body outside the cell bind to the virus. When these antibody-bound viruses enter the cell, they are recognized and tagged as trash by TRIM21, which is then destroyed by the intracellular proteasome.

Utilizing the unique advantages of the TRIM21 protein, it can be used to disrupt Tau protein aggregates associated with AD.

By replacing the virus-binding antibody with a Tau-binding antibody, TRIM21 is redirected so that Tau aggregates are destroyed by the proteasome. It is worth noting that the 'RING' structural domain of the TRIM21 protein is only activated when two or more TRIM21 proteins are aggregated together. Thus, TRIM21 proteins are activated and labeled for destruction only when they bind to neighboring aggregated Tau proteins. Based on this, Trojan horse therapy was proposed and validated.

• Two trojan horse therapies targeting Tau proteins

Novel RING-nanobody therapeutics fuse a nano-antibody that binds to Tau protein with a TRIM21-RING, which is activated when the Tau protein forms aggregates, thereby inducing degradation of the aggregates.

Novel RING-Bait therapy, connecting TRIM21-RING with Tau protein itself. The RING-conjugated Tau protein acts as a bait, which is incorporated into the protein aggregates, and the RING of TRIM21 is then incorporated as well. Once multiple “RING-Bait” are added to the aggregate, they are activated, leading to the disruption of the entire aggregate.

The researchers believe that Tau protein aggregates are hidden inside brain cells and are difficult to degrade. The new TRIM21-based therapeutic can be delivered directly inside the cell, thus degrading Tau aggregates without affecting healthy Tau proteins.

Tackling AD and Other Neurological Diseases

The proposal of Trojan horse therapy has provided a new direction and hope for therapeutic research of neurological diseases such as AD. Efficient removal of phosphorylated Tau is the key to Alzheimer's disease therapeutic strategies, and researchers will need to continue to explore this area in order to comprehensively address neurological diseases such as AD.

As people have a new understanding of the pathogenesis and progression of AD, the development or reuse of drugs that can target different aspects of the pathogenesis of AD has become a hope for the treatment of AD. Creative Biolabs can apply our considerable experience with AD solutions to develop the necessary analytics specific to your neuroscience research project. Please feel free to contact us for more details.

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Alzheimer's Disease