Medalla, Maria

Abstract Tau pathology emerges early in Alzheimer’s disease within entorhinal cortex layer II (ECII) and reaches hippocampal CA1, but how this circuit-level spread translates into sex-dependent vulnerability remains unclear. Using a circuit-defined model in which P301L human tau is expressed selectively in Wolframin-1 (Wfs1 + ) ECII neurons and propagates to CA1, we found that the extent and proximal–distal distribution of tau-positive CA1 neurons were comparable in males and females. Despite similar propagation, females exhibited broad hippocampal-dependent cognitive impairment (working memory, object recognition, fear acquisition, trace associative memory, and contextual fear memory), whereas males showed a selective deficit in trace associative memory. Consistent with these behavioral outcomes, CA1 pyramidal neurons in tau-propagated females displayed reduced excitability (slower action potential kinetics, reduced firing during depolarizing steps) and reduced spontaneous excitatory postsynaptic current (EPSC) amplitude, while males showed subtler intrinsic changes with altered EPSC kinetics. Bulk RNA sequencing of entorhinal cortex and CA1 revealed robust immune pathway engagement after tau propagation, with males showing a stronger Th1/Th2 and neuroinflammatory signature and CTLA4-associated signaling changes, whereas females showed prominent complement–phagosome pathway enrichment and a female-specific increase in Clec7a + microglia density in CA1. CD4 + T-cell infiltration into CA1 was detected in both sexes. Together, these results indicate that sex-specific neuroimmune programs, rather than differences in tau propagation load, shape CA1 electrophysiological dysfunction and the breadth of memory impairment following early entorhinal-to-hippocampal tau spread.

Wolframin-1–positive neurons in the entorhinal cortex of mouse brain propagate tau to the hippocampal CA1 region resulting in memory impairment.

Significance Phase separation of proteins is increasingly thought to play a fundamental role in biological processes. Recent studies show that tau protein phase separates, but the biological significance is unknown since artificial crowding agents are typically used and the resulting tau is not toxic. We now demonstrate that TIA1 potentiates RNA-mediated phase separation of tau, thereby enabling a process that occurs at physiological concentrations and also directs the formation of biologically active, highly neurotoxic oligomeric tau. Coordinated phase separation of functionally related proteins provides a general mechanism through which membraneless organelles can direct biological activities.