Human neuron model identifies potential therapeutic targets for Alzheimer’s disease

Scientists at Weill Cornell Medicine have developed an innovative human neuron model that robustly simulates the spread of tau protein aggregates in the brain—a process that drives cognitive decline in Alzheimer’s disease and frontotemporal dementia. This new model led to the identification of new therapeutic targets that could potentially prevent the spread of tau.

The preclinical study, published April 5 in Cellis a major advance in Alzheimer’s disease research.

Currently, no treatment can stop the spread of tau aggregates in the brains of Alzheimer’s patients. The human neuron model of tau propagation overcomes the limitations of previous models and has revealed potential targets for drug development that were previously unknown.”

Dr. Lee Gan, lead author of the study, director of the Helen and Robert Appel Alzheimer’s Disease Research Institute and the Burton P. and Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine

Human pluripotent stem cells can grow into any cell in the body and can be coaxed into becoming neurons to model brain diseases in a lab dish. However, it was almost impossible to model the spread of tau in these young neurons, as it takes decades for tau to spread in aging brains.

The team of Dr. Gunn used CRISPR technology to modify the genomes of human stem cells, prompting them to express forms of tau associated with diseased aging brains. “This model is a game-changer, simulating the spread of tau in neurons within weeks—a process that would typically take decades in the human brain,” said Dr.

In their effort to stop the spread of tau, the team of Dr. Gan used CRISPRi control to disable a thousand genes to ascertain their role in the spread of tau. They discovered 500 genes that have a significant impact on tau abundance.

“CRISPRi technology has allowed us to use unbiased approaches to search for drug targets without being limited to what has been previously reported by other scientists,” said one of the study’s lead authors Celeste Parra Bravo, a PhD candidate in neuroscience at Weill Cornell Graduate School of Medical. Sciences working in the Gan laboratory.

One breakthrough involves the UFMylation cascade, a cellular process that involves binding a small protein called UFM1 to other proteins. The connection of this process to the spread of tau was previously unknown. Postmortem studies of brains from Alzheimer’s patients found that UFMylation is altered, and the team also found in preclinical models that inhibiting the enzyme required for UFMylation prevents the spread of tau in neurons.

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

Many Alzheimer’s treatments initially show promise in mouse models but fail in clinical trials, Dr. Gunn said. With the new human cell model, she is optimistic about the path ahead. “Our discoveries in human neurons open the door to the development of new treatments that could make a real difference to those suffering from this devastating disease.”