A Rapid Gene Delivery–Based Mouse Model for Early-Stage Alzheimer Disease–Type Tauopathy

The perforant pathway projection from the entorhinal cortex (EC) to the hippocampal dentate gyrus is critically important for long-term memory and develops tau and amyloid pathologies and progressive degeneration starting in the early stages of Alzheimer disease (AD). However, perforant pathway function has not been assessed in experimental models of AD, and a therapeutic agent that protects its structure and function has not yet been identified. Therefore, we developed a new adeno-associated virus–based mouse model for perforant pathway tauopathy. Microinjection into the lateral EC of vectors designed to express either human tau bearing a pathogenic P301L mutation or enhanced green fluorescent protein as a control selectively drove transgene expression in lateral EC layer II perikarya and along the entire rostrocaudal extent of the lateral perforant pathway afferents and dentate terminal field. After human tau expression, hyperphosphorylated tau accumulated only within EC layer II perikarya, thereby modeling Braak stage I of transentorhinal AD tauopathy. Expression of pathologic human tau but not enhanced green fluorescent protein led to specific dose-dependent apoptotic death of perforant pathway neurons and loss of synapses in as little as 2 weeks. This novel adeno-associated virus–based method elicits rapid tauopathy and tau-mediated neurodegeneration localized to the mouse perforant pathway and represents a new experimental approach for studying tau-driven pathogenic processes and tau-based treatment strategies in a highly vulnerable neural circuit.