The spread of tau protein aggregates in the brain—a process that drives cognitive decline in Alzheimer’s disease and frontotemporal dementia—has been studied with a model that incorporates human neurons and captures disease features that ordinarily take decades to unfold. The model has already been used to show that tau propagation is related to a cellular process called the UFMylation cascade. According to in vitro and in vivo experiments, UFMylation-inhibiting drugs could block the spread of tau spread, which could be an effective way to treat Alzheimer’s disease.

Development of the new model was accomplished by Weill Cornell Medical College scientists led by Li Gan, PhD, a professor of neurodegenerative diseases. These scientists also carried out the preclinical experiments that implicated UFMylation in the spread of tau.

Details of this work appeared in the journal Cell, in an article titled, “Human iPSC 4R tauopathy model uncovers modifiers of tau propagation.”

“[We] engineered human induced pluripotent stem cell–derived neuronal lines to express 4R Tau and 4R Tau carrying the P301S MAPT mutation when differentiated into neurons,” the article’s authors wrote. “4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes including shared transcriptomic signatures, autophagic body accumulation, and reduced neuronal activity.”

Human induced pluripotent stem cells can develop into any cell of the body. In the current study, they were coaxed to become neurons to model brain diseases in a lab dish. Moreover, the cells were subjected to genomic modifications that prompted them to express forms of tau associated with diseased aging brains.

“This model has been a game-changer,” Gan asserted. “[It allowed us to simulate] tau spread in neurons within weeks—a process that would typically take decades in the human brain.” Before the current study, it had been nearly impossible to model tau propagation in young neurons.

In their quest to halt tau propagation, Gan’s team employed CRISPRi screening to disable 1,000 genes to ascertain their roles in tau spread. They discovered 500 genetic modifiers of seeding-induced Tau propagation, including retromer VPS29 and genes in the UFMylation cascade.

The UFMylation cascade is a cellular process involving the attachment of a small protein named UFM1 to other proteins. This process’s connection to tau spread was previously unknown.

“In progressive supranuclear palsy and Alzheimer’s disease brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons,” the article’s authors reported. “Inhibiting the UFMylation cascade in vitro and in vivo suppressed seeding-induced Tau propagation. This model provides a robust platform to identify novel therapeutic strategies for 4R tauopathy.”

“CRISPRi technology allowed us to use unbiased approaches to look for drug targets, not confined to what was previously reported by other scientists,” said Celeste Parra Bravo, a lead author of the current study and a neuroscience doctoral candidate in the Gan laboratory.

Currently, no therapies can stop the spread of tau aggregates in the brains of patients with Alzheimer’s disease,” Gan observed. “Our human neuron model of tau spread overcomes the limitations of previous models and has unveiled potential targets for drug development that were previously unknown.”

“We are particularly encouraged by the confirmation that inhibiting UFMylation blocked tau spread in both human neurons and mouse models,” said Shiaoching Gong, PhD, a co-author of the paper and an associate professor of research in neuroscience at Weill Cornell Medicine.

Many Alzheimer’s disease treatments initially show promise in mouse models but do not succeed in clinical trials, Gan remarked. With the new human cell model, she is optimistic about the path ahead: “Our discoveries in human neurons open the door to developing new treatments that could truly make a difference for those suffering from this devastating disease.”

Previous articleBlocking Mechanical Squeeze In Asthma Prevents Inflammatory Cycle
Next articleAACR News: Pancreatic Cancer Outcomes May Improve with Presurgical Nivolumab/Chemo Combo