The Alzheimer’s Virus Protein? How Tau Protein Travels From Brain to Gut
Introduction: The Surprising Gut-Brain Connection in Alzheimer’s
Growing evidence highlights a strong link between gut dysfunction, the gut-brain axis, and the development of Alzheimer’s disease (AD), observed in both patients and animal models. The vagus nerve, a key communication highway in the gut-brain axis, facilitates two-way traffic between the brain and the gut. Years ago, studies revealed that gut inflammation could trigger the local production of Alzheimer’s-related pathological proteins, which then travel via the vagus nerve to the brain, promoting neuropathology and cognitive decline.
But if this is a two-way street, could the reverse also happen? Could pathological proteins from the brain travel to the gut and impact intestinal health? New research provides a compelling answer.
Headline Finding: Pathological Tau Protein Makes the Journey from Brain to Colon
A recent groundbreaking study published in Gut by a team from Seoul National University demonstrates that the tau protein, a key player in Alzheimer’s pathology, can indeed spread from the brain to the gut.
Using Alzheimer’s model mice and a novel colon-chip organoid, the researchers confirmed that the tau protein can travel from the hippocampus to the dorsal motor nucleus of the vagus nerve (DMV) in the brainstem, and then further down to the colon. This propagation of the Alzheimer’s virus protein-like culprit along neural pathways shows how brain pathology can directly influence gut health.
The Mouse Model: Tracing the Tau Protein’s Path
The team used ADLPAPT transgenic mice, which develop both amyloid-beta and tau protein pathologies. Examining 7-month-old mice, they found significant tau tangles in the hippocampus and aggregated, hyperphosphorylated tau protein in the DMV neurons—the very cells that send vagus nerve outputs to the GI tract. Notably, there was no amyloid-beta deposition in this area, mirroring observations in the brainstems of human AD patients.
Crucially, the colon tissue showed similar signs, containing significant levels of both soluble and insoluble tau protein, but almost no APP (the precursor to amyloid-beta). This tau was primarily located in the gut’s own nervous systems: the myenteric and submucosal plexuses. Tracking mice of different ages revealed that tau phosphorylation increased over time, indicating a progressive pathology.
Advanced imaging techniques allowed the researchers to visually confirm that this tau originated in the hippocampus, moved along axons to the DMV, and then continued its journey down the vagus nerve to the colon’s nerve networks—a pathway not observed in healthy wild-type mice.
The Colon Chip: An Innovative Model for the Brain-Gut Axis
To dive deeper into the mechanism, the researchers engineered a sophisticated “colon-chip” organoid—the first in vitro system to successfully mimic the brain-to-gut neural pathway.
This microfluidic device housed three key cell types derived from human induced pluripotent stem cells (iPSCs):
- Vagus motor neurons (VMNs), which grew long axon bundles.
- Gut neurons.
- Colon epithelial cells.
These cells were structured in a 3D model that allowed VMN axons to extend and connect with gut neurons, which in turn sent projections to the epithelial layer, mimicking the natural innervation of the gut.
How the Alzheimer’s Virus Protein Disrupts Gut Health
When the researchers introduced fluorescently tagged tau fibrils (PFFs) into the VMN compartment of the chip, they witnessed the tau protein being actively transported along the axons. It successfully crossed the synapse into the gut neurons, where it accumulated.
This invasion of the Alzheimer’s virus protein-like tau in gut neurons had a direct, damaging consequence: the expression of tight junction proteins in the colon epithelial cells dropped significantly. This compromised the integrity of the gut barrier, leading to increased permeability—a hallmark of a “leaky gut.”
Conclusion and Future Directions: A Systemic View of Alzheimer’s
This study systematically unveils a clear pathway where pathological tau protein hijacks the vagus nerve’s efferent route to travel from the brain to the gut. The accumulation of this Alzheimer’s virus protein-like tau in the colon disrupts the epithelial barrier, potentially explaining AD-related gastrointestinal symptoms like inflammation, barrier instability, and microbiome imbalance.
These findings fundamentally expand our understanding of Alzheimer’s as a more systemic disease. The vagus nerve, identified as a central conduit for tau protein propagation, emerges as a promising future target for therapeutic intervention. Furthermore, the innovative colon-chip model presents a powerful tool for screening drugs that could block this damaging protein transport or protect the delicate gut barrier in Alzheimer’s patients.