Gut-induced alpha-Synuclein and Tau propagation initiate Parkinson's and Alzheimer's disease co-pathology and behavior impairments.

Tau interacts with α-Synuclein (α-Syn) and co-localizes with it in the Lewy bodies, influencing α-Syn pathology in Parkinson's disease (PD). However, whether these biochemical events regulate α-Syn pathology spreading from the gut into the brain remains incompletely understood. Here, we show that α-Syn and Tau co-pathology is spread into the brain in gut-inducible SYN103^+/- and/or TAU368^+/- transgenic mouse models, eliciting behavioral defects. Gut pathology was initially observed, and α-Syn or Tau pathology was subsequently propagated into the DMV or NTS and then to other brain regions. Remarkably, more extensive spreading and widespread neuronal loss were found in double transgenic mice (Both) than in single transgenic mice. Truncal vagotomy and α-Syn deficiency significantly inhibited synucleinopathy or tauopathy spreading. The α-Syn PET tracer [¹⁸F]-F0502B detected α-Syn aggregates in the gut and brain. Thus, α-Syn and Tau co-pathology can propagate from the gut to the brain, triggering behavioral disorders.