Enteric Nervous System Dysfunction as A Key Driver of Alzheimer's Disease Pathogenesis and Progression

摘要

The enteric nervous system(ENS) is a remarkably complex and extensive neural network located within the gastrointestinal(GI) tract, composed of neurons, glia, and immune cells. It plays a critical role in regulating a wide array of digestive processes and local immune responses. Although research on the gut-brain axis has yielded valuable insights, it has historically placed greater emphasis on the roles of gut microbiota dysbiosis and alterations in short-chain fatty acid production as primary mechanisms in neurological and psychiatric disorders. While important, this focus on microbial imbalances has often overshadowed the potential for more direct and intricate connections between the ENS itself and brain pathology. The ENS maintains robust bidirectional communication with the central nervous system(CNS), and its dysfunction is capable of disrupting the gut-brain axis, potentially initiating a cascade of pathological events. Alzheimer's disease(AD), like many other neurological conditions, is frequently associated with various GI symptoms, suggesting that its pathophysiology may involve the ENS. Early studies indicated that amyloid precursor protein(APP) is expressed by enteric neurons and glia, and amyloid-beta(Aβ) plaques have been identified in the GI tract submucosa of AD patients and APP/PS1 transgenic mouse models. However, the existing evidence is not consistent, as other studies have reported conflicting results regarding Aβ pathology in the ENS. Furthermore, observations that APP/PS1 mice do not exhibit significant neuronal degeneration or inflammation in the myenteric plexus even at advanced ages highlight the need for further investigation. Therefore, employing more sophisticated AD animal models is necessary to conclusively determine if and how ENS dysfunction contributes to AD pathogenesis.Using advanced triple-transgenic AD mice that recapitulate a broad spectrum of AD neuropathology, we investigated the ENS-AD connection. We found that oral administration of drugs to block dopamine β-hydroxylase(DBH) or chronically deplete sympathetic nerve terminals in the gut accelerated brain neurodegeneration and promoted the maturation of both Aβ deposits and phosphorylated tau pathology. This GI-specific adrenergic suppression was associated with enhanced neuroinflammation and worsened neurological deficits in behavioral tests. Notably, these effects differed from those of systemic DBH inhibition. DBH suppression also increased tyrosine hydroxylase levels in both GI and brain tissues. Our results demonstrate that dysfunction of GI adrenergic fibers accelerates brain neurodegeneration and Alzheimer's pathology progression. This study establishes ENS dysfunction as a key driver of AD pathogenesis and suggests that norepinephrine from sympathetic fibers exerts an anti-inflammatory effect. Consequently, therapeutic strategies aimed at restoring ENS function and reducing gut-derived inflammation represent a promising avenue for slowing AD progression.

关键词

Alzheimer's disease / enteric nervous system / norepinephrine / dopamine β-hydroxylase / neurodegeneration / tau pathology