Axonal Branch Points of Parvalbumin Interneurons are Focal Sites of Tau-Induced Degeneration

Tau aggregation, a defining feature of tauopathies, commonly appears as neuropil threads within neurites including axons. However, the affected neuronal populations and the spatial organization of axonal vulnerability remain poorly defined. Here, following identification of Tau accumulation in parvalbumin (PV) interneuron axons in primary tauopathy patients, we generated a P301S Tau model targeted to PV interneurons to track the structural integrity of their neurites and somas. We observed neuronal loss alongside axonal dystrophy, with focal swellings forming preferentially at axonal bifurcations. This spatial enrichment exceeded chance levels, and local axonal geometry predicted swelling localization. Longitudinal in vivo imaging revealed that bifurcation-associated swellings progressed to axonal severing. Analogous bifurcation-associated dystrophies were present in PV axons in human primary tauopathy tissue. These findings indicate that axonal branch geometry shapes the spatial pattern of Tau-induced neurodegeneration and identify PV axonal branch points as sites of pathology in mouse and human tauopathy.