Alzheimer’s disease (AD) and other neurodegenerative diseases will have a global impact on health outcomes for people in the coming decades. Without a cure or preventative treatment, it is likely that the economic costs to the U.S. and other countries will be prohibitive, with estimates in the billions of dollars. Thus, understanding the pathophysiology of the disease process will be integral for future therapeutic treatments. The presence of senile plaques and neurofibrillary tangles (NFTs) are hallmarks of Alzheimer’s disease (AD). However, only NFTs have been shown to correlate with the severity of the associated dementia. NFTs have been shown to consist of aggregates of phosphorylated tau protein. Tau normally functions to stabilize microtubules in neuronal processes, but in diseased brain cells tau becomes part of insoluble multi-protein NFT complexes as well as soluble pathogenic oligomers. The progression of the disease follows a well described path initially displaying NFT-associated neurodegeneration in a brain region called the entorhinal cortex followed by neurodegeneration in a downstream brain region - the hippocampus. Importantly, these brain regions are crucial for the formation of long-term memories and are likely responsible for the memory loss observed in AD patients. This proposal will investigate the effect of trans-synaptic spread of pathogenic tau from entorhinal cortical neurons to downstream neurons in the hippocampus. Our preliminary evidence demonstrates that not all neurons in the hippocampus accumulate pathogenic tau and that specific subtypes of neurons in the hippocampus are particularly vulnerable. The experimental design will involve adeno-associated viral vector transfection, immunofluorescence to monitor tau trans-synaptic spread, and the use of cellular electrophysiology to assess the impact that pathogenic tau spread has on vulnerable hippocampal neurons. Importantly, we will also determine the effect of pathogenic tau on network properties of CA1 pyramidal neurons when tau is expressed in select vulnerable neurons. By understanding the resultant changes produced by pathogenic tau at the cellular and network level, it may be possible to develop therapies to counteract these changes at early stages of AD.