Dr. Marco Hefti received a five-year NIH R01 award entitled “A non-canonical role for tau in early human brain development” from the National Institute of Neurological Disorders and Stroke. The award totals $561,007 and the project starts May 1, 2024 and concludes February 28, 2029.

Although best known for its role in Alzheimer disease, the tau protein is a significant driver of neuronal network dysfunction in neurodevelopmental disorders, including epilepsy and autism, which have a devastating lifelong impact on function and quality of life. Tau phosphorylation, detachment from microtubules, and toxic gain of function are significant drivers of pathology in hypoxic-ischemic injury and two of its major developmental sequelae: epilepsy and autism. Despite these toxic effects, tau is strongly evolutionarily conserved through the entire mammalian lineage, suggesting that it has a physiologic function. Although tau knockout has been studied extensively in mice, these studies are difficult to translate to humans because human tau has a unique N-terminus insert in a region critical to tau localization and interaction with NMDA receptors (NMDAR). Tau is a promising therapeutic target for multiple neurodevelopmental diseases, including autism, epilepsy, and early-life hypoxic-ischemic injury. While the efficacy of tau-reducing agents in AD is controversial, they are safe in adults and highly effective at reducing tau levels. This represents an unprecedented opportunity to adapt drugs developed for Alzheimer disease for use in neurodevelopmental disorders. To ensure the safety of this strategy in the developing brain, however, there is a critical need to understand the neurodevelopmental function of the tau protein in an entirely human model system. Without this knowledge, developing safe and effective tau-targeted therapies for these diseases is unlikely. Our long-term goal is to develop safe and effective tau-targeted therapies for neurodevelopmental disorders. Our overall objective for this proposal, as a first step to achieving this goal, is to determine the physiologic role of tau during neurodevelopment. We hypothesize that tau is necessary for dendritogenesis in the developing human brain due to a human-specific N-terminus insert that upregulates tau-NMDAR signaling. This hypothesis is based on our preliminary data demonstrating impaired dendritogenesis in human tau knockout neurons and a vital role for the human-specific tau N-terminus insert in interaction with fyn kinase. It is supported by published literature showing that tau-fyn interaction upregulates NMDAR signaling. This process leads to neurotoxicity in the postnatal brain, but NMDAR signaling is necessary for dendritogenesis and dendritic arborization in the developing brain. We will test our hypothesis by pursuing the following specific aims: (1) Determine the role of tau-NMDAR interaction in human neuronal maturation and (2) Determine the role of the human-specific N-terminus insert in human neurodevelopment. At the completion of the study, our expected outcomes are that we will have identified a critical developmental function of the human tau protein and determined the role of the human-specific n-terminus tau insert. These results will have a significant positive impact because they are a necessary first step to determining the safe window for therapeutic tau reduction in neurodevelopmental disorders and because they would identify a previously unknown human-specific physiologic function of the tau protein.