Author Identifier
Rathnayaka Mudiyanselage Uththara Sachinthanie Senarath: https://orcid.org/0000-0003-4909-6296
Date of Award
2026
Keywords
Alzheimer's disease, short chain fatty acids, medium chain fatty acids, neuroprotective
Document Type
Thesis - ECU Access Only
Publisher
Edith Cowan University
Degree Name
Doctor of Philosophy
School
School of Medical and Health Sciences
First Supervisor
Binosha Fernando
Second Supervisor
Lotta Oikari
Third Supervisor
Prashant Bharadwaj
Fourth Supervisor
Vijay Jayasena
Fifth Supervisor
Ralph Martins
Abstract
There is growing interest in safe, multitargeted metabolic and lipid-based strategies for individuals at risk of, or living with Alzheimer’s disease (AD). Among these, short chain fatty acids (SCFAs) and medium chain fatty acids (MCFAs), particularly sodium butyrate (NaB) and lauric acid (LA), are gaining attention due to their capacity to influence inflammation, antioxidant defence, mitochondrial stability, G protein coupled receptor (GPCR) linked energy sensing and lipid homeostasis, process that are affected early in AD. Despite this potential, the mechanisms through which these metabolites influence human neural cells remain poorly defined.
Current literature suggests that NaB and LA can modulate several biological processes relevant to early AD, but the evidence remains inconclusive. NaB has been reported to reduce pro-inflammatory cytokine activity, increase antioxidant defences, influence mitochondrial metabolism and alter gene expression through histone related mechanisms. LA has shown potential to reduce astrocytic activation, improve oxidative balance and enhance mitochondrial energy use. However, most findings are from rodent studies or simplified cell systems, limiting their relevance to human neural biology. Only a small number of studies have used human induced pluripotent stem cells (iPSC) derived astrocytes or neurons and even fewer have examined the effects of these metabolites under conditions that mimic early amyloid beta (Aβ) associated stress.
To address this gap, this thesis used well established human iPSC derived neural models to systematically investigate the effects of Aβ, NaB and LA on inflammation, antioxidant defences, mitochondrial function, GPCR-mediated cyclic adenosine monophosphate (cAMP) signalling, and lipid metabolism. Accordingly, analyses were conducted in three neural cell types: astrocytes, neurons and spontaneous cultures of astrocytes and neurons. This approach enabled comparison of cell type specific responses with those observed in mixed cell systems.
When exposed to Aβ, neural cell types exhibited distinct differences in their cellular responses. Astrocytes exhibited reduced antioxidant capacity, changes in cytokine expression and alteration in cholesterol associated lipid pathways, consistent with reduced capacity to maintain cellular homeostasis. Neurons were particularly vulnerable, demonstrating significant increases in interleukin-6 (IL-6) and IL-8 expression, substantial adenosine triphosphate (ATP) depletion, instability in GPCR linked signalling and significant alterations in ceramide and sphingolipid profiles. Spontaneous cultures of astrocytes and neurons showed intermediate responses, providing a more physiologically relevant model for early AD related stress. In contrast, treatment with NaB and LA modified Aβ associated changes through complementary mechanisms. NaB was associated with improved mitochondrial performance, modulation of cAMP related energy signalling, reduced inflammatory gene expression and increased lipid classes linked to cellular metabolic stability. LA was associated with reduced cytokine release, maintenance of mitochondrial integrity and alterations in phospholipid and fatty acid pathways indicative of enhanced cellular resilience. When applied in combination, NaB and LA extended these effects across antioxidant activity, signalling balance and lipid homeostasis. Although Aβ related changes were not fully reversed, the combined treatment indicated partial stabilisation of several early metabolic processes.
Collectively, this thesis provides the first integrated molecular and lipidomic evidence in human iPSC derived astrocytes, neurons and spontaneous cultures of astrocytes and neurons, showing that NaB and LA may mitigate key aspects of early Aβ induced dysfunction. These findings highlight the potential of metabolic and lipid based interventions and emphasise the relevance of human iPSC derived systems for mechanistic discovery. Importantly, this work establishes a foundation for future studies incorporating microglia, AD risk genotypes, expanded lipidomic profiling, and in vivo validation to advance SCFA and MCFA based strategies towards clinical application.
Access Note
Access to this thesis is embargoed until 30th May 2031
Recommended Citation
Senarath, R. S. (2026). Assessing neuroprotective effects of short chain fatty acids and medium chain fatty acids in Alzheimer’s disease. Edith Cowan University. https://doi.org/10.25958/2hb4-sp97