A recent groundbreaking study, featured in the journal Science and conducted by researchers at the University of Pennsylvania, has identified a triple motif protein, TRIM11, which plays a crucial role in safeguarding soluble tau monomers from misfolding and irregular aggregation through diverse mechanisms. Notably, patients with AD exhibit markedly reduced levels of TRIM11 in the brain.

The application of TRIM11-targeted therapy demonstrated remarkable effectiveness in counteracting tau pathology and neuroinflammation. It also yielded improvements in cognitive and motor performance across three distinct mouse models, including the widely used AD model mouse 3xTg-AD. These findings indicate that TRIM11 holds significant promise as a potent target for the treatment of tauopathies.

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The preservation of proteins' normal structure and physiological function is governed by a built-in protein quality control system (PQC) found in organisms. This system includes degradation pathways that recycle faulty proteins, molecular chaperones that prevent protein misfolding and aggregation, and depolymerization enzymes that break down pre-existing protein deposits.

Triple motif proteins (TRIMs) constitute a class of proteins distinguished by their cyclic structural domain, B-box motif, and coiled helix structure. Found exclusively in multicellular organisms, more than 70 TRIM proteins have been identified. Some studies suggest that TRIM proteins play a role in PQC mechanisms.

The researchers focused on TRIM in an attempt to find the key to regulating tau proteins in it.

Their analytical approach involved two core strategies. Firstly, they systematically evaluated nearly all known human TRIM proteins to determine their capacity to eliminate tau aggregates from cultured cells. Secondly, they compared TRIM proteins in brain tissue samples from AD patients with varying levels to those from normal control subjects.

The specific tau protein under study was tau P301L, a mutant tau protein found in familial tauopathies. Out of the 75 TRIM proteins analyzed, TRIM10, TRIM11, and TRIM55 exhibited exceptional outcomes, effectively degrading almost all tau P301L aggregates.

Knocking down TRIM10, TRIM11, or TRIM55 using CRISPR technology resulted in an 80130% increase in tau protein aggregation levels, despite unchanged expression levels.

Among the investigated TRIM proteins, TRIM11 demonstrated the most substantial impact, whether through knockdown or overexpression experiments.

Further research encompassed a comparison of mRNA and protein levels of TRIM10, TRIM11, and TRIM55 in brain tissue samples from 23 sporadic AD patients and 14 age-sex matched control brain tissue samples without known neurodegenerative diseases. Strikingly, while mRNA levels of all three remained similar across both groups, TRIM11 protein levels were notably reduced in the brains of AD patients, witnessing a decline of around 55%. Concurrently, immunofluorescence analysis confirmed a decrease in neuron count. Since transcriptional levels of TRIM11 remained unchanged, this points to a post-transcriptional regulatory mechanism.

Further exploration unveiled three mechanisms through which TRIM11 orchestrates the regulation of tau levels.

Firstly, TRIM11 can bind to tau proteins, particularly mutant or hyperphosphorylated tau, and facilitate their ubiquitination, culminating in proteasome-mediated degradation.
Secondly, TRIM11 functions as a molecular chaperone for tau proteins, preventing their misfolding and aggregation.
Lastly, TRIM11 itself can degrade tau proteins and dissolve existing tau protein deposits, showcasing its capability to tackle aberrant tau proteins.

The research team then conducted experiments using the following model mice.
?PS19 mice, a tauopathy model with a common tau mutant P301L, which gradually accumulates tau deposits. PS19 mice were injected with pre-formed tau protofibrils to intensify disease symptoms.
?3xTg-AD mice, expressing tau P301L, APP, and PSEN1 mutations.

Targeted injection of TRIM11 into the hippocampus of 2.5-month-old PS19 mice via AAV9 demonstrated a significant 55% reduction in tau lesions within the brains of treated mice by the age of 10 months. Cognitive testing indicated preserved long-term memory, and the mice displayed enhanced motor skills.

Parallel results were observed in the other two mouse models.

The researchers also administered TRIM11 via cerebrospinal fluid to 3xTg-AD mice, resulting in a 35% reduction in hippocampal tau protein and a 5070% reduction in neurofibrillary tangles. Moreover, the treated mice exhibited improved motor and cognitive performance compared to the controls.

Given that tau protein abnormalities are believed to be more pivotal than A? in AD progression, targeting tau protein emerges as a potent therapeutic avenue. The discovery of TRIM11's pivotal role in regulating tau proteins holds immense promise for advancing AD treatment strategies.

This research takes the pursuit of immortality a step farther. The study found that using Alpelisib, a cancer drug, as a food supplement, can increase the average longevity of healthy mice by 10% starting in middle age, and behave better in old age group.

Alpelisib, an oral small molecule alpha-specific PI3K inhibitor developed by Novartis, was approved for marketing by the FDA in 2019 in combination with Fulvestrant for the treatment of patients with HR+/HER2- advanced or metastatic breast cancer carrying a mutation in the PIK3CA gene.

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Middle-aged healthy mice were fed either a control diet or the same food with the Alpelisib drug added in this investigation. The findings revealed that mice fed an Alpelisib-containing diet not only survived longer, but also exhibited evidence of improved health in old age, such as improved coordination and strength.

Aging is not only about longevity, but also about quality of life, the team said. And this study shows that Alpelisib treatment not only extended the life span of healthy mice, but they also exhibited many signs of healthy aging. The research team is learning more about how these effects occur.

Professor Peter Shepherd, the author of the paper, said, "Alpelisib targets an enzyme called PI3K and we have been working on developing drugs that target PI3K for more than 20 years since studies have revealed that the PI3K pathway is over-activated in many malignancies. It is exciting to see the use of PI3K inhibitors outside of cancer, since this shows novel processes that contribute to age-related disorders, demonstrating the worth of long-term investment in this science."

According to Associate Professor Troy Merry, the paper's corresponding author, it is not recommended that people take this drug for a long time to extend their life because it has some side effects as an anti-cancer drug, such as possibly causing high blood sugar, lung problems, allergic reactions, skin problems, and diarrhea. In addition, various negative effects were observed in this mouse trial, such as potentially creating reduced bone mass in mice. However, this research highlights essential aging pathways and will aid in the development of methods to prolong and maintain healthy longevity. This study also shows some potential applications for short-term Alpelisib treatment of specific metabolic health issues, which the research team is now investigating.

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Industry Spotlight: Innovations in ADC Technology
A recent breakthrough in ADC design involves branched linkers, which improve drug stability and reduce off-target toxicity. Traditional ADCs, like the HER2-targeting T-DM1, faced limitations due to systemic side effects in clinical trials. However, novel linker technologiessuch as those incorporating branched structuresenhance tumor-specific payload delivery, as seen in next-generation ADCs currently under development.

This innovation aligns with the growing demand for precision medicine. For example, biotech companies are now leveraging NHP-derived genomic data to refine ADC pharmacokinetics (PK) and predict human responses more accurately.

The Role of NHPs in Modern Drug Discovery
Cynomolgus monkeys remain a gold standard for translational research. Their genomic DNA is particularly valuable for:
* Biomarker Discovery: Identifying genetic variants linked to disease susceptibility or drug resistance.
* Regulatory Compliance: Regulatory agencies like the FDA often require NHP data to approve first-in-human trials, emphasizing the need for reliable genomic resources.

A biotechnology company recently highlighted that over 80% of late-stage ADC candidates now incorporate NHP-derived data during preclinical phases, underscoring the material's critical role.

Ethical and Sustainable Practices
As the industry evolves, ethical sourcing of NHP biologicals has gained prominence. Organizations are adopting strict guidelines to ensure humane treatment and environmental sustainability, which also enhances data reproducibility.

Looking Ahead
The integration of multi-omics approaches (genomics, proteomics, and metabolomics) with NHP models is poised to accelerate biomarker discovery. Meanwhile, advances in synthetic biology may complementbut not yet replacethe need for primate-derived DNA in complex studies.

In summary, cynomolgus monkey liver genomic DNA remains a vital tool for bridging the gap between lab research and clinical success. As the biopharma industry prioritizes precision and safety, this resource will continue to drive innovations in oncology, immunology, and beyond.

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