Tau-Protecting Protein Identified as Possible Gene Therapy for Alzheimer's Disease

Newly reported research headed by a team at the Perelman School of Medicine at the University of Pennsylvania points to a potential gene therapy approach to neurodegenerative disorders characterized by tangles of tau protein in the brain. Their studies, using human postmortem brain tissue, cell lines, and animal models, showed that administering the gene encoding tripartite motif protein 11 (TRIM11)—a protein linked to tau production—into the brains of mouse models with neurodegenerative diseases similar to AD suppressed deterioration while improving cognitive and motor abilities.

The team’s studies identified TRIM11 as playing a key role in removing the protein tangles that cause tauopathies, including AD, and indicated that TRIM11 plays a key role in protecting against tauopathies, and that its downregulation might contribute to the development of such diseases. Their published paper in Science is titled “TRIM11 protects against tauopathies and is down-regulated in Alzheimer’s disease.” Commenting on the research senior author Xiaolu Yang, PhD, a professor of Cancer Biology at Penn, said, “For the first time, we have identified the gene that oversees tau function, and have a promising target for developing treatments to prevent and slow the progression of Alzheimer’s disease and other related disorders.”

AD is the most common cause of dementia in older adults, with an estimated six million Americans currently living with the disease. It is a progressive brain disorder that slowly destroys memory and thinking skills. One of the underlying causes of neurodegenerative diseases is neurofibrillary tangles (NFTs) of tau proteins, which cause the death of neurons, leading to the symptoms of AD,” the authors explained.

In addition to AD, aggregation of tau proteins into NFTs is associated with over 20 other dementias and movement disorders—collectively known as tauopathies—including progressive supranuclear palsy, Pick’s disease, and chronic traumatic encephalopathy. But how and why tau proteins clump together and form the fibrillar aggregates that make up NFTs in patients with these diseases remains unclear. This major gap in knowledge has made the development of effective therapies challenging for researchers. “The pathogenesis of tauopathies remains unclear, which impedes the development of disease-modifying treatments,” the authors continued.

In fact Alzheimer’s disease (AD) is known as secondary tauopathy , and is additionally characterized by the presence of extracellular amyloid beta (Aß) plaques, the team continued. “Moreover, tau is required for Aß-induced neurotoxicity. Therefore, tau misfolding and aggregation likely represent the main disease-causing event for AD and the other tauopathies,” the investigators pointed out.

“Most organisms have protein quality control [PQC] systems that remove defective proteins, and prevent the mis-folding and accumulation of tangles—like the ones we see with tau proteins in the brain of those with tauopathies—but until now we didn’t know how this works in humans, or why it malfunctions in some individuals and not others,” said Yang. And as the authors continued, “The conversion of tau from soluble monomers to fibrillar aggregates in tauopathies in an age-dependent manner suggests a diminishing capacity of a PQC system that can normally protect against tau aggregation. Nevertheless, the identity and nature of such a PQC system remain undefined.”

Yang and his team, including first author Zi-Yang Zhang, PhD, a postdoctoral researcher in Yang’s lab, previously found that Tripartate motif (TRIM) proteins play an important role in protein quality control in animal cells. For their newly reported study the team examined more than 70 human TRIMs, and identified TRIM11 as playing a major role in suppressing tau aggregation. Their collective experiments, including in vitro tests in which they knocked out different TRIM proteins in cell lines, showed that TRIM11 possesses three main functions related to the quality control of tau proteins. It binds to tau proteins, especially the mutant variants that cause disease, and helps to eliminate them. TRIM11 also acts as a “chaperone” for tau, preventing the proteins from misfolding. And it works to dissolve pre-existing tau aggregates. “TRIM11 promoted the proteasomal degradation of mutant tau as well as superfluous normal tau. It also enhanced tau solubility by acting as both a molecular chaperone to prevent tau misfolding and a disaggregase to dissolve preformed tau fibrils,” the authors explained.

Using postmortem brain tissues of 23 individuals with AD and 14 healthy controls, the researchers validated their findings, and showed that levels of TRIM11 protein are substantially reduced in the brains of individuals with AD, compared with those of healthy control individuals.

To determine the potential utility of TRIM11 as a potential therapeutic agent, the team used an adeno-associated viral vector (AAV) to deliver the TRIM11 gene (AAV9-TRIM11) into the brain of multiple mouse models of tauopathies. They found that animals with tau pathologies receiving the TRIM11 gene exhibited a marked decrease in the development and accumulation of NFTs, and had much improved cognitive and motor abilities. “The up-regulation of TRIM11 through small molecules might be feasible given that its expression appears to be highly regulated,” the team suggested “Moreover, our findings provide a proof of concept for the TRIM11 gene itself as a therapeutic agent, bolstering PQC capacity and thus addressing the root cause of various neurodegenerative tauopathies,” the authors pointed out in their research summary.

“Not only do these findings tell us that TRIM11 could play an important role in protecting people from Alzheimer’s and similar diseases, but we also see that we might be able to develop future therapies that replenish TRIM11 in individuals with lower levels,” added Yang. “We are eager to work with our colleagues to explore the possibility of developing gene therapies that halt the progression of neurodegenerative disease.”

The authors concluded, “The effect of intraparenchymal and intraventricular delivery of AAV9-TRIM11 in animal models provides a proof of concept for the potential utility of the TRIM11 gene to restore protein homeostasis in AD and other tauopathies, thus addressing the root cause of these devastating diseases.”