Hochuli Nathaniel, Kadyan Saurabh, Park Gwoncheol, Patoine Cole, Nagpal Ravinder
The Gut Biome Lab, Florida State University, Tallahassee, FL, 32306, USA.
Department of Health, Nutrition, and Food Sciences, Florida State University, Tallahassee, FL, 32306, USA.
Mol Neurobiol. 2025 May 1. doi: 10.1007/s12035-025-04960-z.
Chronic psychological stress is a known risk factor for neurodegenerative disorders like Alzheimer's disease (AD), but its role in AD neuropathology remains unclear. Using the water-avoidance stress model in the APP/PS1 preclinical mouse model of AD, we investigate how chronic stress exacerbates neurobehavioral dysfunction and cognitive impairment and explore the neuroprotective potential of indole-3-propionate (IPA), a microbiome-derived metabolite, in mitigating these effects. Our findings show that psychological stress leads to depression- and anxiety-like behaviors, as indicated by reduced grooming and exploration behaviors; however, these effects are ameliorated by IPA supplementation. Stress also disrupts the gut microbiome and promotes intestinal inflammation. While IPA does not significantly alter microbiome composition, it mitigates inflammation by normalizing IL-17a and TGF-β gene expression and reducing TNF-⍺ and IL-6 protein levels. Although stress has a limited effect on hippocampal inflammation, IPA suppresses low-grade neuroinflammation by downregulating IL-1β, TNF-⍺, IL-6, and MCP-1 protein levels. Additionally, IPA treatment tends to reduce hippocampal amyloid-β plaques. These findings highlight the detrimental effects of chronic psychosocial stress on AD pathology and suggest that IPA may confer neuroprotection through the gut-immune-brain axis, supporting the therapeutic potential of microbial metabolites in mitigating cognitive decline.
慢性心理应激是阿尔茨海默病（AD）等神经退行性疾病的已知风险因素，但其在AD神经病理学中的作用仍不清楚。在AD临床前小鼠模型APP/PS1中使用避水应激模型，我们研究了慢性应激如何加剧神经行为功能障碍和认知障碍，并探索了微生物群衍生代谢物吲哚-3-丙酸（IPA）在减轻这些影响方面的神经保护潜力。我们的研究结果表明，心理应激会导致类似抑郁和焦虑的行为，表现为梳理和探索行为减少；然而，补充IPA可改善这些影响。应激还会破坏肠道微生物群并促进肠道炎症。虽然IPA不会显著改变微生物群组成，但它通过使IL-17a和TGF-β基因表达正常化并降低TNF-α和IL-6蛋白水平来减轻炎症。尽管应激对海马体炎症的影响有限，但IPA通过下调IL-1β、TNF-α、IL-6和MCP-1蛋白水平来抑制低度神经炎症。此外，IPA治疗倾向于减少海马体淀粉样β斑块。这些发现突出了慢性心理社会应激对AD病理的有害影响，并表明IPA可能通过肠-免疫-脑轴赋予神经保护作用，支持微生物代谢物在减轻认知衰退方面的治疗潜力。
