This new study, published in Science Translational Medicine, presents an innovative nasal spray treatment that has shown promising results in clearing harmful tau protein build-up and improving cognitive functions in aged mice models.
“This nasal spray approach opens new avenues for non-invasive delivery of tau therapeutic antibodies directly to the brain, and it holds promise for many neurodegenerative diseases,” said Dr. Rakez Kayed, lead author and professor at the Department of Neurology at UTMB.
Tau is a microtubule-associated protein found in the brain that helps stabilize microtubules, which are part of the framework that maintains cell shape and organization in neurons. In healthy brains, tau proteins keep things orderly.
However, in neurodegenerative diseases, they can become abnormally twisted and form tangles that disrupt neuronal function and lead to cognitive decline. Current tau immunotherapies have struggled with efficacy due to their limited ability to penetrate the intracellular compartments where these tau buildups reside.
Kayed and his team developed a specific type of antibody, TTCM2, which selectively recognizes and targets toxic tau buildup. This antibody was packaged in particles to enhance its delivery to the brain via the nasal route.
“Our research highlights the potential of nasal tau immunotherapy to effectively target intracellular tau aggregates—a primary driver of neurodegeneration and cognitive decline in diseases like Alzheimer’s and other tauopathies,” added Kayed. “This method not only improves the delivery of therapeutic antibodies but also enhances their efficacy in clearing tau aggregates and improving cognitive functions.”
A crucial aspect of this approach is the involvement of TRIM21, an intracellular receptor for antibodies and E3 ligase, known for mediating the clearance of antibody-bound pathogens like viruses. In the study, TRIM21 facilitated the clearance of antibody-bound intracellular tau aggregates, thereby enhancing the therapeutic effect and cognitive improvements in the mice model.
“This advancement could significantly impact the treatment strategies for Alzheimer’s and related tauopathies, offering new hope for millions of patients suffering from these debilitating conditions,” said Sagar Gaikwad, first author of the study and postdoctoral fellow at UTMB.
The study’s findings highlight the potential impact on future treatments for neurodegenerative diseases. UTMB researchers plan to advance this research by conducting further preclinical trials and exploring the potential of TTCM2-ms in human clinical trials. The goal is to translate these promising results into a viable treatment option for patients suffering from Alzheimer’s disease and other tau-related disorders.
What causes tau protein build-up in the human brain?
Tau protein build-up in the human brain typically occurs due to abnormal changes in the protein’s structure and function. Here’s a breakdown of the process:
1. Tau Protein Function:
- Tau proteins normally play a crucial role in stabilizing microtubules, which are part of the cytoskeleton in neurons. These microtubules help maintain the structure of the cell and facilitate the transport of nutrients and other molecules within the neuron.
2. Phosphorylation of Tau:
- Tau proteins are regulated by the process of phosphorylation, where phosphate groups are added to the protein. In a healthy brain, this process is tightly controlled. However, in Alzheimer’s disease, tau becomes hyperphosphorylated, meaning too many phosphate groups are added.
3. Aggregation of Hyperphosphorylated Tau:
- Hyperphosphorylated tau proteins lose their ability to bind to microtubules properly. As a result, they detach and start to accumulate inside neurons, forming aggregates called neurofibrillary tangles (NFTs). These tangles disrupt the normal functioning of neurons, leading to cell damage and death.
4. Genetic and Environmental Factors:
- Several factors can contribute to the abnormal phosphorylation and aggregation of tau:
- Genetic mutations: In some cases, mutations in the MAPT gene, which encodes the tau protein, can increase the likelihood of tau dysfunction.
- Aging: The risk of abnormal tau accumulation increases with age, possibly due to a decline in the brain’s ability to clear misfolded proteins.
- Inflammation: Chronic inflammation in the brain can exacerbate tau pathology by activating enzymes that promote tau phosphorylation.
- Oxidative stress: Imbalances in free radicals and antioxidants in the brain can lead to tau protein misfolding.
- Head injuries: Traumatic brain injuries are linked to increased tau accumulation, possibly due to the disruption of normal cellular processes.
5. Spread of Tau Pathology:
- Once tau proteins start to aggregate, they can spread from one neuron to another, contributing to the progression of Alzheimer’s disease. This spread is thought to follow a prion-like mechanism, where misfolded tau induces normal tau to misfold and aggregate.
6. Consequences for Brain Function:
- The accumulation of tau tangles disrupts the communication between neurons and eventually leads to neuron death. This contributes to the cognitive decline observed in Alzheimer’s patients, including memory loss, confusion, and difficulty with problem-solving.
Understanding the precise mechanisms that lead to tau pathology is a major focus of current Alzheimer’s research, with the hope that targeting these processes might offer new therapeutic strategies.