Parkinson's and Alzheimer's Diseases May Originate in the Gut!

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Parkinson’s and Alzheimer’s Diseases May Originate in the Gut!

Parkinson’s and Alzheimer’s Diseases May Originate in the Gut!

Parkinson’s disease and Alzheimer’s disease are both neurodegenerative conditions that severely impact the quality of life in elderly individuals.

Surprisingly, these two diseases share some common pathological features, particularly the abnormal accumulation of two key proteins—alpha-synuclein and Tau—in both the brain and gut.

This raises critical questions: how do these proteins travel from the gut to the brain, and how do they contribute to the dual pathology of Parkinson’s and Alzheimer’s?

On September 5, 2024, a research team from the Fourth Military Medical University’s Department of Neurobiology published a study in the journal Neuron titled “Gut-induced alpha-Synuclein and Tau propagation initiate Parkinson’s and Alzheimer’s disease co-pathology and behavior impairments.”

The study investigates the mechanisms by which alpha-synuclein and Tau spread from the gut to the brain, leading to shared pathological features of Parkinson’s and Alzheimer’s. This process results in motor, cognitive, and emotional impairments.

Parkinson's and Alzheimer's Diseases May Originate in the Gut!

Protein Spread from the Gut to the Brain

To understand how alpha-synuclein and Tau migrate from the gut to the brain, researchers developed transgenic mice models that specifically express fragments of alpha-synuclein (N103) and Tau (N368) in the gut neurons. They used CRISPR-Cas9 technology to insert genes into the mice that are triggered by tetracycline to express these protein fragments, tagged with a red fluorescent protein (RFP) marker. Upon tetracycline feeding, alpha-synuclein and Tau accumulate in the gut neurons.

The researchers monitored the expression and aggregation of these proteins in the gut and brain at 0, 2, and 10 months. Using immunofluorescence staining and other methods, they quantified the distribution of these proteins in neurons of the gut, motor areas, and other brain regions. They also assessed the mice’s motor skills, cognitive function, and emotional behaviors. To verify protein aggregation, a new alpha-synuclein PET probe (F0502B) was used to image alpha-synuclein accumulation in vivo and ex vivo.

Gut Protein Aggregation

In the gut of these transgenic mice, the RFP-tagged alpha-synuclein N103 and Tau N368 fragments showed increasing accumulation over time, forming aggregates. This was especially evident in the SYN103+/ and TAU368+/ mice, where RFP signals intensified alongside alpha-synuclein and Tau immunostaining. These changes were accompanied by severe gastrointestinal dysfunction, such as constipation.

Transmission to the Brain

The study revealed that these RFP-labeled protein fragments could spread from the gut to the brain via the vagus nerve. At the initial 0-month time point, these fragments appeared in the dorsal motor nucleus and nucleus of the solitary tract, then gradually spread to other regions such as the striatum, entorhinal cortex, and anterior cingulate cortex. Notably, endogenous alpha-synuclein and Tau in the brain also began to aggregate, leading to significant loss of motor neurons and other types of neurons.

Behavioral Impairments

The “Both” mice, which expressed both alpha-synuclein N103 and Tau N368, exhibited severe motor coordination deficits, learning and memory impairments, and anxiety-like behavior. In the rotarod test, these mice showed pronounced motor dysfunction between 2 to 10 months. In the water maze test at 10 months, they took longer to escape, indicating spatial memory impairment. Additionally, they displayed reduced object recognition in memory tests. These findings highlight that the mice developed motor, cognitive, and emotional disturbances simultaneously.

PET Imaging

To confirm alpha-synuclein aggregation, the researchers used the novel PET probe F0502B, which detected alpha-synuclein accumulation in the intestines of the “Both” and SYN103+/ mice, particularly in the ileum, cecum, and colon. Imaging and biodistribution experiments also confirmed that F0502B could specifically detect alpha-synuclein aggregation in the brains of these mice. This suggests that PET imaging could be a valuable tool for early diagnosis of alpha-synuclein accumulation in the gut, opening new avenues for clinical diagnosis and prevention.

Conclusion

The study demonstrates that alpha-synuclein and Tau can travel from the gut to the brain via the vagus nerve, triggering endogenous protein aggregation and leading to the shared pathology of Parkinson’s and Alzheimer’s diseases.

This finding not only explains the overlapping pathological features of these diseases but also offers a new perspective on their mechanisms.

Protein transmission from the gut to the brain could be a key factor in the onset of both conditions.

Link to the full study