Tau-Regulating Protein: A New Hope for Alzheimer’s Treatment

As the protein levels of TRIM11 decrease in Alzheimer’s disease models, recent research from Penn Medicine proposes that supplementing this protein could bolster cognitive and motor abilities.

Uncovered in a groundbreaking study from the Perelman School of Medicine at the University of Pennsylvania, a gene responsible for encoding a protein associated with tau production – tripartite motif protein 11 (TRIM11) – appears to halt the decline in smaller animal models of Alzheimer-like neurodegenerative diseases.

Simultaneously, it also enhances cognitive and motor function. Remarkably, TRIM11 has shown to have a significant role in the elimination of protein tangles triggering neurodegenerative diseases, such as Alzheimer’s.

Alzheimer’s disease, the leading cause of dementia in the elderly, affects an estimated 6 million Americans. This relentless brain disorder gradually impairs memory and cognitive skills.

New research from Penn Medicine, headed by Virginia M.Y. Lee, PhD, and the late John Q. Trojanowski, MD, PhD, sheds light on one of the fundamental triggers of neurodegenerative diseases – neurofibrillary tangles (NFTs) formed by tau proteins. These tangles are detrimental to neurons and lead to Alzheimer’s disease symptoms, such as memory loss.

The role of the TRIM11 protein in Alzheimer’s brain

In earlier research, Yang’s team, including first author Zi-Yang Zhang, PhD, discovered that TRIM proteins are critical for protein quality control in animal cells.

Upon examining over 70 human TRIMs, they identified TRIM11 as playing a pivotal role in suppressing tau aggregation.

TRIM11 has three primary functions regarding tau proteins’ quality control. It binds to tau proteins, particularly the disease-causing mutant variants, and aids in their removal. It serves as a tau “chaperone,” averting mis-folding of the proteins.

Lastly, TRIM11 breaks down pre-existing tau aggregates.

Can replenishing TRIM11 protein improve cognitive and motor function?

Using post-mortem brain tissues from 23 Alzheimer’s patients and 14 healthy controls from the Center for Neurodegenerative Disease Research tissue bank, researchers confirmed these findings, noting significantly lower TRIM11 protein levels in Alzheimer’s patients compared to healthy controls.

To assess TRIM11’s therapeutic potential, the researchers employed an adeno-associated viral vector, a common gene therapy tool, to deliver the TRIM11 gene into multiple mouse models’ brains.

The results were striking; mice with tau pathologies that received the TRIM11 gene showed a drastic reduction in NFT development and accumulation, with significantly improved cognitive and motor abilities.

“Not only do these findings tell us that TRIM11 could play an important role in protecting people from Alzheimer’s and similar diseases,” adds Yang, “but we also see that we might be able to develop future therapies that replenish TRIM11 in individuals with lower levels.

“We are eager to work with our colleagues to explore the possibility of developing gene therapies that halt the progression of neurodegenerative disease.”

Source: 10.1126/science.add6696

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