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

Scientific paper - Original scientific paper

• Author: Jan Homolak
• Author: Joke De Busscher
• Author: Miguel Zambrano-Lucio
• Author: Mihovil Joja
• Author: Davor Virag
• Author: Ana Babić Perhoč
• Author: Ana Knezović
• Author: Jelena Osmanović Barilar
• Author: Melita Šalković-Petrišić
• Author's institution: University of Zagreb; School of Medicine; (Department of Pharmacology)
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences; Pharmacology

Abstract (english)

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.

• Keywords (english): Alzheimer Disease / metabolism; Animals; Brain / metabolism; Disease Models, Animal; Goblet Cells / metabolism; Mucins / adverse effects; Mucins / metabolism; Mucus; Rats
• Language: english
• Publication type: Scientific paper - Original scientific paper
• Publication status: Published
• Peer review: Peer review
• Publication version: Published version
• Journal title: ACS Chemical Neuroscience
• Numbering: vol. 14, no. 15, pp. 2667-2682
• p-ISSN: 1948-7193
• e-ISSN: 1948-7193
• DOI: https://doi.org/10.1021/acschemneuro.3c00223
• URN:NBN: urn:nbn:hr:105:161445
• Publication: 2023-08-02
• Document URL: https://pubs.acs.org/doi/10.1021/acschemneuro.3c00223
• Type of resource: Text
• Access conditions: Open access
• Created on: 2024-09-25 10:59:16