In a remarkable moment for Alzheimer’s disease research, scientists at Weill Cornell Medicine have developed an innovative human neuron model that successfully simulates the spread of tau protein aggregates in the brain, a function that triggers cognitive decline in AD and frontotemporal dementia.
Tau proteins— found in the nerve cells of our brains— support the structure of neurons and their normal functioning. However, in some cases, such as patients with Alzheimer’s disease, tau proteins can become abnormal. They tend to clump together in neurons, disrupting the transport of nutrients and other molecules throughout the cell. This can eventually lead to the death of the neuron.
The research team’s new model has led to the identification of novel therapeutic targets that could potentially block the harmful propagation of tau.
“Currently no therapies can stop the spread of tau aggregates in the brains of patients with Alzheimer’s disease,” said Dr. Li Gan, director of the Helen and Robert Appel Alzheimer’s Disease Research Institute at Weill Cornell Medicine and the study’s lead author, in a statement. “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.”
CRISPR to the rescue
Previous attempts to model tau propagation in the lab using human pluripotent stem cells have been challenging. This is due to tau aggregation being a process that typically takes decades to unfold in the aging human brain.
Dr. Gan’s team used CRISPR genome engineering to modify human stem cells, prompting them to express forms of tau associated with diseased brains. “This model has been a game-changer, simulating tau spread in neurons within weeks— a process that would typically take decades in the human brain,” Dr. Gan explained.
With this powerful new model in hand, the researchers employed CRISPR interference (CRISPRi) screening. This screening method systematically disables over a thousand genes and assesses their impact on tau abundance. The unbiased approach led to the discovery of 500 genes influencing tau propagation.
“CRISPRi technology allowed us to use unbiased approaches to look for drug targets, not confined to what was previously reported by other scientists,” said lead study author Celeste Parra Bravo, a neuroscience doctoral candidate at Weill Cornell.
One particularly encouraging finding was the connection between the UFMylation cellular process and tau spread. UFMylation involves the attachment of a small protein named UFM1 to other proteins.
Post-mortem studies of Alzheimer’s patient brains revealed UFMylation to be altered. Further experiments in the human neuron model and mouse models showed that inhibiting the enzyme required for UFMylation effectively blocked tau propagation.
Tackling an unmet need
“We are particularly encouraged by the confirmation that inhibiting UFMylation blocked tau spread in both human neurons and mouse models,” said paper co-author Dr. Shiaoching Gong, associate professor at Weill Cornell.
Many promising Alzheimer’s treatments have failed to succeed in clinical trials after showing promise in mouse models. However, the researchers are optimistic that the new human neuron platform will improve the odds of translation.
“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,” said Dr. Gan.
The team’s research was published in the journal Cell.
