Dual Effects: Intrastriatal Injection of alpha-syn N103/tau N368 Preformed Fibrils Promotes Endogenous alpha-synuclein Aggregates in the Proximal Colon

Background: Pathological changes in the brain can affect the gastrointestinal tract, whereas there is less evidence regarding the brain-gut axis. Objective: To identify whether cerebral endogenous phosphorylated alpha-synuclein induces gastrointestinal dysfunction via the brain-gut axis, mediated by the vagus nerve. Methods: alpha-syn N103/tau N368 preformed fibrils were injected into the dorsal lateral striatum of rodents, and the cerebral and colonic synucleinopathies and changes in the enteric nervous system were analyzed. Moreover, subdiaphragmatic vagotomy was conducted to confirm the role of the vagus nerve in brain-gut propagation. Results: An anterograde propagation of phosphorylated alpha-synuclein from the brain to the proximal colon mainly via the vagus nerve was observed at one month. The accumulation of phosphorylated alpha-synuclein was detected in the proximal colon over time, accompanied by infiltration of macrophages and eosinophils in the mucosa and submucosa. Upon injection with lower doses of preformed fibrils, the accumulation of phosphorylated alpha-synuclein and dopaminergic neuron loss was reduced to levels consistent with control at six months, while the expression levels of GFAP, Iba-1, and IL-6 increased. Under high preformed fibrils dose conditions, fecal traits and gastrointestinal motility were significantly reduced at six months, and aggregations of phosphorylated alpha-synuclein and an increasing level of IL-1 beta appeared. Conclusion: Induced endogenous alpha-synuclein can quickly propagate into the proximal colon mainly via the vagus nerve. Injections of low doses of preformed fibrils can elicit recovery of the enteric nervous system and degradation of alpha-synuclein aggregates whereas high doses cause accumulation of pathological alpha-synuclein, enteric inflammation, and prominent gastrointestinal dysfunction.