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.