TY - JOUR
T1 - Altered Secretion, Constitution, and Functional Properties of the Gastrointestinal Mucus in a Rat Model of Sporadic Alzheimer's Disease
AU - Homolak, Jan
AU - De Busscher, Joke
AU - Zambrano-Lucio, Miguel
AU - Joja, Mihovil
AU - Virag, Davor
AU - Babic Perhoc, Ana
AU - Knezovic, Ana
AU - Osmanovic Barilar, Jelena
AU - Salkovic-Petrisic, Melita
N1 - Funding
This work was funded by the Croatian Science Foundation(IP-2018-01-8938). The research was co-financed by the Scientific Centre of Excellence for Basic, Clinical,and Translational Neuroscience (project “Experimental and clinical research of hypoxic-ischemic damage in perinatal and adult brain”; GA KK01.1.1.01.0007, funded by the European Uniont hrought he European Regional Development Fund
PY - 2023/8/2
Y1 - 2023/8/2
N2 - 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.
AB - 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.
KW - Alzheimer’s disease
KW - brain−gut axis
KW - mucus
KW - neurodegeneration
KW - streptozotocin
UR - http://www.scopus.com/inward/record.url?scp=85166391276&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/37477640
U2 - 10.1021/acschemneuro.3c00223
DO - 10.1021/acschemneuro.3c00223
M3 - Article
C2 - 37477640
SN - 1948-7193
VL - 14
SP - 2667
EP - 2682
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 15
ER -