Gut-Induced Alpha-Synuclein and Tau Propagation Initiate Parkinson’s and Alzheimer’s Disease Co-Pathology and Behavior Impairments
Gastrointestinal-Induced Spread of α-Synuclein and Tau Proteins Triggers Comorbid Pathology and Behavioral Impairments in Parkinson’s and Alzheimer’s Diseases
Background
Parkinson’s Disease (PD) and Alzheimer’s Disease (AD) are two common neurodegenerative disorders, caused by the aggregation of α-synuclein (a-syn) and Tau protein in the brain, respectively, forming abnormal inclusions. Braak and colleagues proposed a hypothesis suggesting that the pathogenic protein a-syn in PD might first aggregate in the enteric nervous system (ENS) of the gastrointestinal tract and then spread upward to the central nervous system (CNS) via the vagus nerve. However, conventional PD models face technical bottlenecks in accurately simulating the spread of pathogenic proteins from the gastrointestinal tract to the brain. Therefore, establishing more realistic models to better study the pathological mechanisms of this process has become a focus of academic interest.
Research Overview and Publication Source
This study is a collaborative effort by scholars from the Fourth Military Medical University in Xi’an, Xijing Hospital, and Shenzhen Institute of Advanced Technology, among others. The research findings were published in the 2024 issue of the journal Neuron. The authors utilized a transgenic mouse model to explore the mechanism of a-syn and Tau protein aggregation in the ENS induced by the gastrointestinal tract and their propagation to the brain via the vagus nerve. This study is the first to demonstrate the potential dual pathological pathways of a-syn and Tau propagation in both the gut and brain.
Research Methods
The study established a transgenic mouse model induced by the gastrointestinal tract to simulate the spread of a-syn and Tau proteins from the gut to the brain. Specific methods included:
Model Construction: Using the Tet-On system, researchers constructed a double-gene knock-in transgenic mouse model expressing a-syn N103 and Tau N368 tagged with red fluorescent proteins. These pathogenic proteins were induced by oral tetracycline and expressed in the ENS of mice, allowing observation of their accumulation in the gut and brain at different time points.
Protein Expression Detection: Mice underwent gastrointestinal tissue staining at 0, 2, and 10 months, detecting the distribution of RFP-tagged a-syn and Tau proteins in different gut regions, confirming specific expression of both proteins in the ENS. A wild-type mouse control group was set to exclude possible interference from antibiotics and showed no abnormal accumulation of a-syn or Tau proteins.
Aggregation Detection and Brain Propagation: Immunofluorescence staining was used to detect the distribution of a-syn and Tau proteins in the dorsal motor nucleus of the vagus (DMV), nucleus of the solitary tract (NTS), loci such as the locus coeruleus, hippocampus, and other brain regions. Results showed these proteins diffused from the gut to the brain. Further using the newly developed a-syn PET tracer [^18F]-F0502B, in vivo PET-CT imaging was performed on mice, observing the accumulation of a-syn in the gut and brain.
Neuronal Loss and Behavioral Testing: The study analyzed motor function, cognitive function, and anxiety-like behavior in transgenic mice. Using tests like the rotarod, Morris water maze, and open field test, mice exhibited motor dysfunction, spatial memory deficits, and anxiety behaviors within 0 to 10 months post a-syn and Tau protein accumulation, simulating behavioral symptoms observed in PD and AD patients.
Vagus Nerve Severing Experiment: Researchers confirmed the critical role of this neural pathway in protein spread through a vagus nerve severing experiment. After severing the vagus nerve, the accumulation of a-syn and Tau proteins in mice’s brains significantly reduced, and neuronal loss decreased, further validating the neurobiological mechanism of gut-to-brain propagation.
Research Results
The research results demonstrated a multi-step process of a-syn and Tau proteins propagating from the gut to the brain, accompanied by significant neuronal damage and behavioral abnormalities:
Protein Aggregation: a-syn N103 and Tau N368 gradually accumulated in the gastrointestinal tract and formed visible aggregates in tissue sections, with the aggregation level increasing over time. In highly expressed areas (colon, cecum), a-syn and Tau proteins exhibited noticeable co-localization.
Propagation Pathway: After aggregation in the gut, proteins gradually spread to the DMV and NTS and further expanded to areas such as the locus coeruleus (LC), hippocampus (HC), and substantia nigra within 2 months. Double-gene knock-in mice displayed more extensive spread and more severe neuronal loss, indicating a-syn and Tau coexistence might enhance their propagation capability.
Neuronal Loss and Functional Impairment: During propagation, mouse brain regions such as the substantia nigra, anterior cingulate cortex, and locus coeruleus showed significant neuronal density reduction, consistent with PD pathology. Moreover, the aggregation of a-syn and Tau led to behavioral abnormalities in transgenic mice, including decline in motor function, spatial memory loss, and anxiety-like behavior, symptoms closely related to PD and AD in humans.
PET Imaging Detection: The a-syn accumulation in mice was visualized using the [^18F]-F0502B tracer. This tracer showed high signals in PET-CT imaging of the gut and brain, validating its potential as an early detection tool.
Validation of Vagus Nerve Role: Vagus nerve severing surgery reduced protein spread and accumulation in the brain, while also decreasing neuronal loss, confirming the vital role of the vagus nerve in the protein propagation pathway.
Research Conclusion
The gastrointestinal-induced transgenic mouse model constructed in this study truly replicated the pathological process of a-syn and Tau spreading from gut to brain, revealing the synergistic effects of both on neuronal damage and behavioral abnormalities. Key findings include that a-syn and Tau proteins can co-aggregate in the gastrointestinal tract and propagate via the vagus nerve to the brain, leading to extensive neuronal loss and behavioral impairments. This discovery not only deepens the understanding of the pathological mechanisms of PD and AD but also provides new perspectives for early clinical diagnosis and intervention.
Research Significance and Value
The significance of this study lies in its innovative modeling approach and in-depth exploration of protein spread from the gastrointestinal tract to the brain. Through the transgenic mouse model, the research exhibited the possible early pathological processes of PD and AD, reinforcing the potential role of the gastrointestinal tract in the onset of neurodegenerative diseases. Additionally, using [^18F]-F0502B as a PET tracer for imaging detection of protein aggregation in the gut and brain demonstrated potential practical applications, providing a new direction for the future diagnosis of Parkinson’s and Alzheimer’s diseases.
Research Highlights
- Innovative Model: The gut-induced a-syn and Tau transgenic mouse model based on the Tet-On system for the first time replicated the protein propagation pathway from the gastrointestinal tract to the brain, providing a reliable tool for subsequent research.
- Advancements in Imaging Technology: The developed [^18F]-F0502B PET tracer allows in vivo detection of a-syn aggregation, offering potential means for early screening of Parkinson’s disease.
- Importance of the Vagus Nerve: Experiments validated the crucial role of the vagus nerve in the protein propagation process, providing a theoretical basis for targeted therapy approaches aimed at the vagus nerve.
Future Outlook
Future studies should continue to explore the mechanisms of propagation from the gastrointestinal tract to the brain, particularly other possible pathways. Moreover, improving PET imaging technology to enhance spatial resolution will help better illustrate the pathological distribution in specific brain regions.