Humanized tau and amyloid-β deposition accelerate tau propagation, neuronal cell loss and neurophysiological dysfunction in novel mouse models of primary age-related tauopathy and Alzheimer’s disease

Abstract In Alzheimer’s disease (AD), tau pathology arises in entorhinal cortex layer II (ECII) and advances through defined hippocampal circuits to CA1 and connected neocortical regions, yet the determinants of this hierarchical spread remain unclear. We previously established a circuit-defined propagation model by expressing Cre-inducible human P301L 2N4R tau selectively in Wolframin-1 (Wfs1)+ ECII neurons using AAV-FLEX-TauP301L in Wfs1-Cre mice. Here, to test how amyloid-β (Aβ) and human tau background shape propagation, we generated human MAPT knock-in Wfs1 mice and APPNL-G-F/MAPT double knock-in Wfs1 mice (T-Wfs1 and AT-Wfs1) and induced ECII-restricted TauP301L expression. Three months after injection, phosphorylated or misfolded tau-positive neurons were enriched in proximal CA1 in Wfs1 and T-Wfs1 mice, resembling primary age-related tauopathy, whereas AT-Wfs1 mice showed preferential accumulation near the CA1/subiculum (Sub) boundary, consistent with an AD-like pattern. In T-Wfs1 and AT-Wfs1 mice, tau spread extended through Sub to neocortical regions, and phosphorylated tau accumulated predominantly in excitatory rather than inhibitory neurons. Electrophysiological analyses revealed increased spontaneous neuronal firing and impaired GABAergic transmission in the CA1/Sub boundary and neocortical areas in T-Wfs1 and AT-Wfs1 mice, indicative of impaired GABAergic input and enhanced neuronal excitability in these regions. Together, these data indicate that human MAPT and Aβ pathology shift the circuit topography of tau propagation and are associated with early network dysfunction, supporting a synergistic interaction that promotes AD-like spread and synaptic imbalance. Competing Interest Statement The following authors have competing financial interests: T.I. is on SAB of AAVINE and consults for Takeda and Otsuka Pharma.