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

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.

Insights into Gastrointestinal Redox Dysregulation in a Rat Model of Alzheimer’s Disease and the Assessment of the Protective Potential of D-Galactose

“…Previous experiments have revealed that duodenal goblet cells in the STZ-icv rat model of AD do not respond to cholinergic stimulation for mucus secretion . This study builds upon those findings by demonstrating that the GI tracts in STZ-icv rats also exhibit reduced responsiveness to an oxidative environment and exposure to D-galactose.…”

“…In transgenic animal models of AD, it is common to observe physiological changes in the GI tract before observing any pathological changes in the brain. − This sequence of events makes it difficult to study the GI consequences of localized neurodegeneration in the CNS. On the other hand, brain-first nontransgenic animal models, which involve the targeted delivery of toxic substances (e.g., amyloid β, streptozotocin (STZ), colchicine, and okadaic acid) that mimic AD-related neuropathology to the CNS, provide an opportunity to investigate the one-way disruption of the gut–brain axis. − These models offer invaluable insights into how localized neurodegeneration impacts the structural and functional integrity of the gut. One of the most extensively studied and well-established brain-first models of sporadic AD is the rat model generated by intracerebroventricular administration of the diabetogenic toxin streptozotocin (STZ-icv). , Based on the evidence accumulated over the last 30 years, the STZ-icv model recapitulates key behavioral and neuropathological hallmarks of AD .…”

“…40 Interestingly, dysfunctional gut−brain axis and pathophysiological changes in the gut were also reported in this model, indicating that it represents a valid platform for investigating the GI consequences of neurodegeneration affecting the CNS. The STZ-icv gut is characterized by violated structural and functional properties of the GI barrier, 41 distorted secretion and constitution of gut mucus, 24 redox dyshomeostasis, 22,42 and altered absorption. 43 In this study, we focused on redox homeostasis as oxidative stress plays a key etiopathogenetic role in neurodegenerative diseases, 9,44−46 including AD.…”

Exploratory Study of Gastrointestinal Redox Biomarkers in the Presymptomatic and Symptomatic Tg2576 Mouse Model of Familial Alzheimer’s Disease: Phenotypic Correlates and Effects of Chronic Oral d-Galactose

“…ABTS (7 mM) was incubated with K 2 S 2 O 8 (2.45 mM) for 24 h. ABTS/K 2 S 2 O 8 solution was diluted 40-fold and incubated with 1 μL of each homogenate in a volumetric ratio of 1:100 (sample/ABTS). The absorbance at 405 nm was measured after 5 min using an Infinite F200 PRO multimodal microplate reader (Tecan, Switzerland) . The difference between the baseline control solution (ABTS) and final absorbance was proportional to the sample antioxidant capacity .…”

“…Accumulating evidence suggests that the gut might play an important role in the etiopathogenesis and progression of Alzheimer’s disease (AD). , Gastrointestinal (GI) alterations have been reported in both transgenic − and nontransgenic animal models of AD. − Importantly, GI alterations often precede neuropathological changes in the brain and correlate with disease progression, , suggesting that pathophysiological processes in the gut might contribute to dyshomeostasis in the central nervous system (CNS) in the early stages of neurodegeneration. Honarpisheh et al reported that GI dysfunction takes place before the onset of cognitive symptoms and the accumulation of cerebral amyloid-β (Aβ) in the (6 months old) Tg2576 mouse model of familial AD .…”