α-Synuclein modulates tau spreading in mouse brains

alpha-Synuclein (alpha-syn) and tau aggregates are the neuropathological hallmarks of Parkinson's disease (PD) and Alzheimer's disease (AD), respectively, although both pathologies co-occur in patients with these diseases, suggesting possible crosstalk between them. To elucidate the interactions of pathological alpha-syn and tau, we sought to model these interactions. We show that increased accumulation of tau aggregates occur following simultaneous introduction of alpha-syn mouse preformed fibrils (mpffs) and AD lysate-derived tau seeds (AD-tau) both in vitro and in vivo. Interestingly, the absence of endogenous mouse alpha-syn in mice reduces the accumulation and spreading of tau, while the absence of tau did not affect the seeding or spreading capacity of alpha-syn. These in vivo results are consistent with our in vitro data wherein the presence of tau has no synergistic effects on alpha-syn. Our results point to the important role of alpha-syn as a modulator of tau pathology burden and spreading in the brains of AD, PDD, and DLB patients.

Automated summary

The neuropathological hallmarks of Parkinson's disease (PD) and Alzheimer's disease (AD), alpha-synuclein (alpha-syn) and tau aggregates, may interact in patients with these diseases, with alpha-syn playing an important modulatory role in the burden and spreading of tau pathology.