Impact of Genotype and High-Fat High-Carbohydrate Diet on the Colon in the TgF344-AD and 5xFAD Rodent Models 公开
Schwartz, Noah (Spring 2023)
Abstract
Background
Elevated levels of soluble amyloid beta, accumulation of amyloid plaques, neuronal cell death, and inflammation are main features of Alzheimer’s disease (AD) pathology in the central nervous system (CNS). While the presentation of AD in the CNS is well characterized, a gap in understanding exists in how AD pathology displays in the enteric nervous system (ENS). The literature supports peripheral chronic inflammation contribution to the exacerbation of brain AD pathology, but little is known about the specific role of the ENS in the onset and progression of AD.
Methods
Here we investigated how the genotype for AD and high-fat high-carbohydrate diet (HFHC) intake interacts to impact the ENS. The colon tissue of 5xFAD female mice (2 months of age) and TgF344-AD female and male rats (6 and 15 months of age) were assessed with immunoassays and western botting to evaluate the presence of genotype-dependent hallmarks of AD identified in the brain including: soluble amyloid, key neuronal marker protein expression, and inflammation. For genotype-diet interactions, 5xFAD mice were fed a HFHC diet for 8 weeks to investigate the impact of a known inflammation-inducing environmental factor on AD pathology in the intestine. Behavioral tests for fecal transit were performed.
Results
The colon of the 5xFAD female mice did not present detectable soluble amyloid in the colon at 4 months of age, suggesting diet-genotype interaction did not impact the soluble amyloid concentrations in the colon. The TgF344-AD rat model presented intestinal soluble amyloid. TgF344-AD rats also demonstrate an age-dependent increase in interferon gamma (IFN-γ, a proinflammatory cytokine shown to contribute to increases in amyloid concentrations in the CNS). HFHC diet regulates inflammatory markers IL-1β, CXCL1, and IL-5 in 5xFAD mice. Additionally, a decrease in fecal water content was observed in HFHC-fed 5xFAD mice.
Conclusions
Our novel findings support a genotype effect on AD pathology in the intestine of the TgF344-AD rat model. While the mechanisms contributing to presentation of AD pathology in the ENS require future studies to define, possible factors include the unique AD-linked mutations and the mouse prion promotor driving expression of APP and PSEN1 genes in the transgenic rats.
Our findings in the 5xFAD mouse model suggest that a HFHC diet may modulate inflammation of the intestine in a manner independent of amyloid production. Additionally, HFHC diet contributes to constipation, a symptom of GI disorders frequently associated with intestinal inflammation. Collectively, our findings are an important step to improving our understanding of intestinal AD pathology and how it impacts the disease overall.
Keywords: Amyloid beta, Enteric nervous system, Peripheral inflammation, Intestine, Colon
Table of Contents
Table of Contents
Abstract…………………………………………………………………………………………..1
Introduction…………………………………………………………………………………….. 3
Methods………………………………………………………………………………………….. 8
Results…………………………………………………………………………………………... 12
Discussion………………………………………………………………………………………. 16
Figures………………………………………………………………………………................20
References………………………………………………………………………………………. 25
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