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bioRxiv · 10.1101/2023.07.27.550831

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

Homolak, J.·Varvaras, K.·Sciacca, V.·Perhoc, A. B.·Virag, D.·Knezovic, A.·Barilar, J. O.·Salkovic-Petrisic, M.
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Abstract

IntroductionRecent evidence suggests that the gut plays a vital role in the development and progression of Alzheimers disease (AD) by triggering systemic inflammation and oxidative stress. The well-established rat model of AD, induced by intracerebroventricular administration of streptozotocin (STZ-icv), provides valuable insights into the GI implications of neurodegeneration. Notably, this model leads to pathophysiological changes in the gut, including redox dyshomeostasis, resulting from central neuropathology. Our study aimed to investigate the mechanisms underlying gut redox dyshomeostasis and assess the effects of D-galactose, which is known to benefit gut redox homeostasis and alleviate cognitive deficits in this model. Materials and MethodsDuodenal rings isolated from STZ-icv animals and control groups were subjected to a prooxidative environment using AAPH or H2O2 with or without D-galactose in oxygenated Krebs buffer ex vivo. Redox homeostasis was analyzed through protein microarrays and functional biochemical assays, alongside cell survival assessment. Structural equation modeling, univariate, and multivariate models were employed to evaluate the differential response of STZ-icv and control samples to the controlled prooxidative challenge. ResultsSTZ-icv samples showed suppressed expression of catalase and glutathione peroxidase 4 (GPX4) and increased baseline activity of enzymes involved in H2O2 and superoxide homeostasis. The altered redox homeostasis status was associated with an inability to respond to oxidative challenges and D-galactose. Conversely, the presence of D-galactose increased antioxidant capacity, enhanced catalase and peroxidase activity, and upregulated superoxide dismutases in the control samples. ConclusionSTZ-icv-induced gut dysfunction is characterized by a diminished ability of the redox regulatory system to maintain long-term protection through the transcription of antioxidant response genes, as well as compromised activation of enzymes responsible for immediate antioxidant defense. D-galactose can exert beneficial effects on gut redox homeostasis under physiological conditions.

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Homolak, J., Varvaras, K., Sciacca, V., Perhoc, A. B., Virag, D., Knezovic, A., Barilar, J. O., Salkovic-Petrisic, M.. 2023-07-28. Insights into Gastrointestinal Redox Dysregulation in a Rat Model of Alzheimer's Disease and the Assessment of the Protective Potential of D-galactose. https://doi.org/10.1101/2023.07.27.550831

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