Altered secretion, constitution, and functional properties of the gastrointestinal mucus in a rat model of sporadic Alzheimer's disease

Homolak, J.; De Busscher, J.; Zambrano Lucio, M.; Joja, M.; Virag, D.; Babic Perhoc, A.; Knezovic, A.; Osmanovic Barilar, J.; Salkovic-Petrisic, M.

doi:10.1101/2022.10.03.510623

bioRxiv · 10.1101/2022.10.03.510623

Altered secretion, constitution, and functional properties of the gastrointestinal mucus in a rat model of sporadic Alzheimer's disease

Homolak, J.·De Busscher, J.·Zambrano Lucio, M.·Joja, M.·Virag, D.·Babic Perhoc, A.·Knezovic, A.·Osmanovic Barilar, J.·Salkovic-Petrisic, M.

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Abstract

Accumulating evidence supports the involvement of the gastrointestinal (GI) system in Alzheimers 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 of the disease. The GI mucus system is a possible mediator of GI dyshomeostasis in neurological disorders as 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) to dissect the efferent (i.e. brain-to-gut) effects of isolated central neuropathology on the GI mucus system. Quantification and 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 glycoprotein aggregation and binding capacity in vitro. Finally, functional consequences of the reduced barrier-forming capacity of the 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 characterized by the insensitivity to neurally-evoked mucosal secretion, altered mucus constitution, and reduced barrier-forming capacity potentially increasing the susceptibility of STZ-icv rat model of AD to GI and systemic inflammation induced by intraluminal toxins, microorganisms, and drugs.

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Homolak, J., De Busscher, J., Zambrano Lucio, M., Joja, M., Virag, D., Babic Perhoc, A., Knezovic, A., Osmanovic Barilar, J., Salkovic-Petrisic, M.. 2022-10-05. Altered secretion, constitution, and functional properties of the gastrointestinal mucus in a rat model of sporadic Alzheimer's disease. https://doi.org/10.1101/2022.10.03.510623

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