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Article

Duodenal α-Synuclein PFF Injection Induces Vagus-Related Gut-to-Brain Pathology in C57BL/6J and A53T Transgenic Mice

by
Mengfei Wang
1,2,
Guangqiang Sun
2,3,
Peifeng Wan
2,
Zitong Wang
2,
Yali Nie
2,
Hongchun Liu
3,
Meiyu Geng
2,3,
Ming Liu
1,2,* and
Yu Zhang
2,3,*
1
Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
2
Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China
3
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
*
Authors to whom correspondence should be addressed.
Brain Sci. 2026, 16(8), 804; https://doi.org/10.3390/brainsci16080804
Submission received: 24 June 2026 / Revised: 17 July 2026 / Accepted: 19 July 2026 / Published: 30 July 2026
(This article belongs to the Special Issue Advances in Parkinson’s Disease)
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Abstract

Background: The Braak hypothesis proposes that α-synuclein (α-syn) pathology may originate in the gastrointestinal tract and propagate to the central nervous system along the gut–brain axis; however, the precise propagation routes and the factors influencing this process remain controversial. Methods: A gut-originating Parkinson’s disease model was established by injecting α-syn preformed fibrils (PFF) into the duodenal muscularis of C57BL/6J and A53T transgenic mice. Phosphorylated α-synuclein (p-α-syn) pathology, motor behavior, and gut microbiota were assessed, with truncal vagotomy included to evaluate its association with gut-to-brain propagation. Results: In C57BL/6J mice, at 4 months post-injection, p-α-syn deposition was observed in both the duodenal muscular layer and the striatum, accompanied by gut microbiota alterations and motor behavioral deficits. Truncal vagotomy was associated with reduced p-α-syn levels in the brain and alterations in the gut microbiota. In A53T transgenic mice, p-α-syn pathology and neurodegenerative changes were also observed following α-syn PFF injection, though the lack of a genetically matched wild-type control precludes definitive attribution of these phenotypes solely to the A53T transgene. Conclusions: These results align with the Braak hypothesis, showing that gut-derived p-α-syn pathology and associated functional impairments are intimately linked to vagal pathways during their propagation to the brain. Additionally, this gut-origin PD mouse model may serve as a useful tool for future mechanistic investigations.
Keywords: Parkinson’s disease; Braak hypothesis; α-Synuclein; preformed fibrils; vagus nerve; gut microbiota; A53T Parkinson’s disease; Braak hypothesis; α-Synuclein; preformed fibrils; vagus nerve; gut microbiota; A53T
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MDPI and ACS Style

Wang, M.; Sun, G.; Wan, P.; Wang, Z.; Nie, Y.; Liu, H.; Geng, M.; Liu, M.; Zhang, Y. Duodenal α-Synuclein PFF Injection Induces Vagus-Related Gut-to-Brain Pathology in C57BL/6J and A53T Transgenic Mice. Brain Sci. 2026, 16, 804. https://doi.org/10.3390/brainsci16080804

AMA Style

Wang M, Sun G, Wan P, Wang Z, Nie Y, Liu H, Geng M, Liu M, Zhang Y. Duodenal α-Synuclein PFF Injection Induces Vagus-Related Gut-to-Brain Pathology in C57BL/6J and A53T Transgenic Mice. Brain Sciences. 2026; 16(8):804. https://doi.org/10.3390/brainsci16080804

Chicago/Turabian Style

Wang, Mengfei, Guangqiang Sun, Peifeng Wan, Zitong Wang, Yali Nie, Hongchun Liu, Meiyu Geng, Ming Liu, and Yu Zhang. 2026. "Duodenal α-Synuclein PFF Injection Induces Vagus-Related Gut-to-Brain Pathology in C57BL/6J and A53T Transgenic Mice" Brain Sciences 16, no. 8: 804. https://doi.org/10.3390/brainsci16080804

APA Style

Wang, M., Sun, G., Wan, P., Wang, Z., Nie, Y., Liu, H., Geng, M., Liu, M., & Zhang, Y. (2026). Duodenal α-Synuclein PFF Injection Induces Vagus-Related Gut-to-Brain Pathology in C57BL/6J and A53T Transgenic Mice. Brain Sciences, 16(8), 804. https://doi.org/10.3390/brainsci16080804

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