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

Jan Homolak*, Joke De Busscher, Miguel Zambrano-Lucio, Mihovil Joja, Davor Virag, Ana Babic Perhoc, Ana Knezovic, Jelena Osmanovic Barilar, Melita Salkovic-Petrisic

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

Abstract

The gastrointestinal (GI) system is affected in Alzheimer's disease (AD); however, it is currently unknown whether GI alterations arise as a consequence of central nervous system (CNS) pathology or play a causal role in the pathogenesis. GI mucus is a possible mediator of GI dyshomeostasis in neurological disorders as the CNS controls mucus production and secretion via the efferent arm of the brain-gut axis. The aim was to use a brain-first model of sporadic AD induced by intracerebroventricular streptozotocin (STZ-icv; 3 mg/kg) to dissect the efferent (i.e., brain-to-gut) effects of isolated central neuropathology on the GI mucus. Morphometric analysis of goblet cell mucigen granules revealed altered GI mucus secretion in the AD model, possibly mediated by the insensitivity of AD goblet cells to neurally evoked mucosal secretion confirmed by ex vivo cholinergic stimulation of isolated duodenal rings. The dysfunctional efferent control of the GI mucus secretion results in altered biochemical composition of the mucus associated with reduced mucin glycoprotein content, aggregation, and binding capacity in vitro. Finally, functional consequences of the reduced barrier-forming capacity of the mucin-deficient AD mucus are demonstrated using the in vitro two-compartment caffeine diffusion interference model. Isolated central AD-like neuropathology results in the loss of efferent control of GI homeostasis via the brain-gut axis and is characterized by the insensitivity to neurally evoked mucosal secretion, altered mucus constitution with reduced mucin content, and reduced barrier-forming capacity, potentially increasing the susceptibility of the STZ-icv rat model of AD to GI and systemic inflammation induced by intraluminal toxins, microorganisms, and drugs.

Original languageEnglish
Pages (from-to)2667-2682
Number of pages16
JournalACS Chemical Neuroscience
Volume14
Issue number15
Early online date21 Jul 2023
DOIs
Publication statusPublished - 2 Aug 2023

Keywords

  • Alzheimer’s disease
  • brain−gut axis
  • mucus
  • neurodegeneration
  • streptozotocin

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