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

Tau aggregation, a hallmark of tauopathies, often manifests as neuropil threads within neurites, including axons. While the specific neuronal populations and spatial organization of axonal vulnerability are not well understood, a recent study has shed light on this aspect. Researchers identified Tau accumulation in parvalbumin (PV) interneuron axons of primary tauopathy patients and developed a P301S Tau model specifically targeted to these PV interneurons. This allowed them to monitor the structural integrity of their neurites and somas.

The investigation revealed neuronal loss alongside axonal dystrophy, with a notable spatial enrichment of these abnormalities occurring at axonal bifurcations. This spatial enrichment was statistically significant, suggesting that it was not due to chance. Furthermore, the local axonal geometry was found to predict the localization of these swellings. Long-term in vivo imaging demonstrated that these bifurcation-associated swellings ultimately led to axonal severing.

Interestingly, similar bifurcation-associated dystrophies were observed in PV axons of human primary tauopathy tissue, further supporting the findings. These results indicate that the geometry of axonal branches plays a crucial role in shaping the spatial pattern of Tau-induced neurodegeneration. Additionally, the study highlights PV axonal branch points as potential sites of pathology in both mouse and human tauopathies.