Nanoscopic tau aggregates in Parkinson’s disease

Abstract Post-mortem tau pathology is frequently observed in Parkinson’s disease (PD) using immunohistochemistry (IHC) to measure large inclusions. However, small protein aggregates that precede inclusions are considered a major driver of toxicity in neurodegenerative disease. We aimed to uncover the distribution of nanoscopic aggregates across six brain regions in post-mortem tissue from 14 PD cases, 7 cases with age-related tau deposition, and 8 neuropathology-free controls using the single-molecule pull-down assay (SiMPull). In the hippocampus and amygdala, tau aggregates were detected by SiMPull that correlated with tau IHC immunostaining. Despite negligible IHC-labelled aggregates in the putamen, we identified a population of high-intensity nanoscopic tau aggregates in PD using SiMPull, labelled by 10–1000 antibodies per aggregate and 30–800 nm in length. Nanoscopic tau aggregate burden in PD resembled mid-Braak-stage Alzheimer’s disease and appeared to precede inclusions. Meanwhile, SiMPull did not detect a PD-specific population of nanoscopic αSyn aggregates, and instead detected low-order multimers. Finally, tau aggregation was associated with Lewy Body load and dementia status in PD.