Pathological tau propagation from the brain to the colon via the vagal efferent pathway in Alzheimer’s disease

Background Alzheimer’s disease (AD) is a neurodegenerative disorder marked by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles, leading to cognitive decline. Recent research has highlighted the involvement of the gut–brain axis (GBA) in AD progression, suggesting that the disease may also affect the gut. Objective To investigate the transmission of tau from the brain to the gut via the vagus nerve and its impact on gut function, we aimed to develop a novel in vitro system to simulate the GBA. Design We used an AD animal model to examine the spread of tau from the brain to the colon. We also established an innervated colon-on-a-chip model to replicate the key components of the GBA, including vagal motor neurons, enteric neurons and colon epithelial cells. Results In ADLP APT mice, we observed tau aggregates in the nerve plexuses of the colon and confirmed that tau spreads from the hippocampus to the dorsal motor nucleus of the vagus and enteric neurons in the colon. This tau transmission was barely observed in ADLP APT mice with vagotomy, suggesting the possibility of a neural pathway through which tau pathology can propagate from the brain to the colon. The colon-on-a-chip system effectively mimicked this pathway, showing that tau could be transmitted along the vagal motor neuron to enteric neurons and impact colon epithelium stability. Conclusions This study demonstrates that tau pathology can propagate from the brain to the colon via the vagus nerve, providing evidence supporting the brain-to-gut axis in AD.