Early Aβ-induced changes in the enteric nervous system and the gut: structure, function, and motility

Alzheimer’s disease is increasingly recognized as affecting not only the central nervous system but also the autonomic nervous system, comprising the enteric nervous system, and thus the gut. Given the structural and functional similarities between the enteric and central nervous system, including susceptibility to Aβ, this study investigated the early and acute effects of monomeric Aβ on primary enteric neurons in vitro and on intestinal motility ex vivo . Acute Aβ application caused marked neuronal hyperexcitability, with increased spike frequencies and calcium influx, and led to enhanced intestinal contractility without altering frequency or timing. Prolonged 72-hour exposure did not induce cell death or apoptosis but significantly reduced neurite outgrowth and decreased synaptic markers and beta II tubulin. These findings suggest that acute Aβ primarily drives the excitability of enteric neurons and intestinal motility, while prolonged exposure subsequently leads to structural and synaptic changes. Overall, the study points to early dysfunction of the enteric nervous system in Alzheimer’s disease and highlights the gut as a potential target for early interventions.