In a significant advancement for Alzheimer’s disease research, Cornell scientists have developed an innovative human neuron model that robustly simulates the spread of tau protein, a key pathogen in Alzheimer’s disease. This new model has led to the identification of novel therapeutic targets that could potentially block tau spread, offering hope for new treatments that could truly make a difference for those affected by the disease.
The research, published in the journal Cell, was led by Dr. Li Gan, the 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 at Weill Cornell Medicine. Dr. Gan’s team used CRISPR technology to modify the genomes of human stem cells, prompting them to express forms of tau associated with diseased aging brains. This allowed them to simulate tau spread in neurons within weeks, a process that would typically take decades in the human brain.
The new human cell model overcomes the limitations of previous models and has unveiled potential targets for halting tau propagation. The team employed CRISPRi screening to disable 1,000 genes to ascertain their roles in tau spread and discovered 500 genes that have a significant impact on tau abundance. One discovery includes the UFMylation cascade, 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, but post-mortem studies of brains from patients with Alzheimer’s disease found that UFMylation is altered, and the team also found in preclinical models that inhibition of the enzyme required for UFMylation blocks tau propagation in both human neurons and preclinical models.