Altered Secretion, Constitution, and Functional Properties of the Gastrointestinal Mucus in a Rat Model of Sporadic Alzheimer's Disease

The gastrointestinal (GI) system is affected in Alzheimer'sdisease (AD); however, it is currently unknown whether GI alterationsarise as a consequence of central nervous system (CNS) pathology orplay a causal role in the pathogenesis. GI mucus is a possible mediatorof GI dyshomeostasis in neurological disorders as the CNS controlsmucus production and secretion via the efferent arm of the brain-gutaxis. The aim was to use a brain-first model of sporadic AD inducedby intracerebroventricular streptozotocin (STZ-icv; 3 mg/kg) to dissectthe efferent (i.e., brain-to-gut) effects of isolated central neuropathologyon the GI mucus. Morphometric analysis of goblet cell mucigen granulesrevealed altered GI mucus secretion in the AD model, possibly mediatedby the insensitivity of AD goblet cells to neurally evoked mucosalsecretion confirmed by ex vivo cholinergic stimulation of isolatedduodenal rings. The dysfunctional efferent control of the GI mucussecretion results in altered biochemical composition of the mucusassociated with reduced mucin glycoprotein content, aggregation, andbinding capacity in vitro. Finally, functional consequences of thereduced barrier-forming capacity of the mucin-deficient AD mucus aredemonstrated using the in vitro two-compartment caffeine diffusioninterference model. Isolated central AD-like neuropathology resultsin the loss of efferent control of GI homeostasis via the brain-gutaxis and is characterized by the insensitivity to neurally evokedmucosal secretion, altered mucus constitution with reduced mucin content,and reduced barrier-forming capacity, potentially increasing the susceptibilityof the STZ-icv rat model of AD to GI and systemic inflammation inducedby intraluminal toxins, microorganisms, and drugs.