The roles of nutritional factors and gut-brain axis in the pathogenesis of psychiatric disorders: Implications on Alzheimer’s disease and ADHD

Abstract

This dissertation aims to investigate the potential links between metabolic dysregulation, the gut-brain axis, and neurodegenerative diseases. It comprises three chapters that focus on exploring the effects of vitamin D deficiency on Alzheimer's disease (AD) amyloidopathy and gliopathy, examining the impact of a high-fat diet (HFD) on dopaminergic dysregulation, REM sleep fragmentation, and attention-deficit hyperactivity disorder (ADHD)-like behaviors and the causal relationship between slow gut transition and AD pathology. In Chapter 1, I explored the role of vitamin D in AD pathology. Lower serum vitamin D levels have been associated with higher AD risk, but the underlying mechanisms remain unclear. My findings suggested that vitamin D plays a crucial role in modifying the course of AD by regulating amyloid pathology. Vitamin D deficiency led to an increase in brain amyloid-beta (Aβ) levels and changes in gene expression, while vitamin D supplementation reduced Aβ levels and improved memory function. Furthermore, I found that vitamin D deficiency exacerbated Aβ pathology and increased GABA-positive reactive astrocytes, whereas vitamin D supplementation ameliorated these effects. These results suggested that vitamin D could be a potential preventive and therapeutic nutritional approach for AD. In Chapter 2, I examined the effects of a high-fat diet (HFD) on dopaminergic dysregulation and behavioral deficits in male mice. The HFD group showed decreased ii wakefulness, fragmented REM sleep, ADHD-like behaviors, including anxiety, anhedonia, hyperactive-like behaviors, and impaired visuospatial memory. Additionally, the HFD group had decreased mRNA levels of dopamine-related genes in the brain regions of dopaminergic reward circuits. My findings suggest that HFD-induced behavioral deficits and disturbed REM sleep are associated with dysregulation of the dopaminergic system. Chapter 3 focused on the relationship between slow gut transition and AD pathology. Epidemiological studies have suggested a high prevalence of constipation in neurodegenerative disorders, including AD. My findings supported the notion that slow gut transition leads to a leaky gut, resulting in systemic inflammation and accelerated amyloidopathy. Importantly, this study also found that loperamide-induced slow gut transition caused memory impairment in wildtype mice. The study provided critical insights into the potential role of maintaining gut health in AD prevention and treatment. This dissertation investigated the links between metabolic dysregulation, the gut-brain axis, and neurodegenerative diseases, focusing on the effects of vitamin D deficiency, high-fat diets, and slow gut transition on various pathological aspects. The findings suggest that vitamin D plays a crucial role in modifying AD progression by regulating amyloid pathology and gliopathy, while high-fat diets lead to dopaminergic dysregulation, disturbed REM sleep, and ADHD-like behaviors. Additionally, the slow gut transition was found to exacerbate AD pathology through systemic inflammation and accelerated amyloidopathy. These results highlight the potential of nutritional interventions and maintaining gut health as preventive and therapeutic approaches for AD and other neurodegenerative disorders.