Induction of Intracellular Tau Aggregation Is Promoted by α-Synuclein Seeds and Provides Novel Insights into the Hyperphosphorylation of Tau

Intracytoplasmic proteinaceous inclusions, primarily composed of tau or alpha-synuclein (alpha-syn), are predominant pathological features of Alzheimer's disease (AD) and Parkinson's disease (PD), respectively. However, the coexistence of these pathological aggregates is identified in many neurodegenerative disorders, including spectrum disorders of AD and PD. Whereas alpha-syn can spontaneously polymerize into amyloidogenic fibrils, in vitro, tau polymerization requires an inducing agent. The current study presents a human-derived cellular model, in which recombinant, preformed alpha-syn fibrils cross-seed intracellular tau to promote the formation of neurofibrillary tangle-like aggregates. These aggregates were hyperphosphorylated, Triton insoluble, and thioflavin-S positive, either comingling with endogenously expressed alpha-syn aggregates or induced by only exogenously applied recombinant alpha-syn fibrils. Furthermore, filamentous, amyloidogenic tau took over the cellular soma, displacing the nucleus and isolating or displacing organelles, likely preventing cellular function. Although a significant proportion of wild-type tau formed these cellular inclusions, the P301L mutation in tau increased aggregation propensity resulting from alpha-syn seeds to over 50% of total tau protein. The role of phosphorylation on the development of these tau aggregates was investigated by coexpressing glycogen synthase kinase 3 beta or microtubule-associated protein/microtubule affinity-regulating kinase 2. Expression of either kinase inhibited the formation of alpha-syn-induced tau aggregates. Analyses of phosphorylation sites suggest that multiple complex factors may be associated with this effect and that Triton-soluble versus Triton-insoluble tau may be independently targeted by kinases. The current work not only provides an exceptional cellular model of tau pathology, but also examines alpha-syn-induced tau inclusion formation and provides novel insights into hyperphosphorylation observed in disease.