Assessment of a novel tau propagation pathway from layer II medial entorhinal cortical neurons to CA1 pyramidal neurons as an early Braak stage mouse model

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Abnormally phosphorylated microtubule-associated protein tau (p-tau) is one of the diagnostic hallmarks of AD pathologies, which strongly correlates with synaptic loss and cognitive decline in AD. Tau pathology first appears in the transentorhinal cortex and entorhinal cortex layer II (EC II), then spreads to the Cornu Ammonis 1 (CA1) field of the hippocampal region at the prodromal stage of AD (Braak stage I-II). However, no animal model has ever succeeded in showing tau propagation from EC II specific to CA1 as typically seen in the early Braak staging. A recent study has discovered that Wolfram syndrome-1 (Wfs1) positive cells in EC II project to CA1 via the stratum lacunosum moleculare along the temporammonic (TA) pathway. We hypothesize that misfolded tau propagates from Wfs1+ cells in EC II to CA1 via the TA pathway, and that the TA pathway is a novel therapeutic target to suppress tau propagation in the prodromal AD stage. Our exciting preliminary data showed that the stereotaxic injection of adeno-associated virus expressing Cre-inducible P301L tau into EC II of Wfs1-Cre mice induced: 1) robust human tau transfer from EC II to CA1 pyramidal neurons, 2) direct tau transfer between axonal terminals of Wfs1+ EC II neurons and dendrites of CA1 pyramidal neurons, 3) suppression of excitability of CA1 pyramidal neurons, and 4) impaired associative working memory. Thus, this new mouse model may recapitulate tau pathology progression from Braak I to II, and develop neurophysiological dysfunction and hippocampal learning impairment. The object of this current application is to fully characterize the pathology of this EC II-CA1 tau propagation mouse model and delineate the connectivity and mode of tau transmission from EC II to CA1. Our overarching goal is to invent therapeutics for prodromal AD using this mouse model. In Aim 1, we will i) characterize the post-translational modification of tau and cell types in EC II-CA1 mice using multiple p-tau antibodies and neuronal specific markers. ii) Validate the translatability of the findings in human AD brain tissues using early Braak stage and age/sex matched control specimens.iii) Investigate the gene expression profiles in EC, CA1, and prefrontal cortical regions of male and female mice to understand the molecular basis of sexual dimorphism in the behavioral outcome. In Aim 2, we will i) employ immuno-electron microscopy and super-resolution confocal microscopic imaging to capture tau transfer between EC II axonal terminals and radial dendrites of CA1 pyramidal neurons;ii) explore monosynaptic tracing between CA1 pyramidal cells and EC II neurons using Cre-dependent complementation of a modified rabies virus and WGA-GFP reporter system, and iii) determine the effect of activating/inhibiting neuronal firing on tau propagation, the role of neuronal extracellular vesicle release, and LDL Receptor Related Protein 1 as the predicted receptor for free tau secreted from the synaptic terminals. The proposed research project will develop a new understanding of tau propagation mechanism seen in the early Braak stages and provide a new insight for the sexual dimorphism in cognitive phenotype.