Abstract
Alzheimer's disease (AD) is a complex multifactorial brain disorder characterised by dementia, neurodegeneration, plaques and neurofibrillary tangles in elderly people. The identification of the key cellular and molecular mechanisms that culminate in these disease-associated phenotypes is vital for the development of effective treatment strategies. Most research highlights the importance of amyloid-beta, tau and other interacting genes and proteins as the cause of these phenotypes. Nevertheless, there is no significant cure yet, despite centennial efforts in the AD field. Modern AD theory elaborates on other factors, including metabolic dysfunction, infection, inflammation and vascular disorders. Systems medicine approach offers the integration of these factors into a comprehensive AD model, by utilization of omics data. This perspective also fits nicely with the drug repurposing field that takes advantage of known pharmaceutical molecules to create novel treatment options. So far, systems medicine studies have shown productive results in the understanding and treatment of other complex metabolic disorders.The purpose of this thesis is to systematically investigate the genetic and metabolic underpinnings of AD compared to healthy ageing by leveraging a systems medicine approach to determine novel biomarkers and ptential therapeutic targets. Gene co-expression network analysis and genome-scale metabolic modelling were utilized to determine brain marker genes and metabolites, respectively. The primary source for the discovery was the transcriptome data of two AD cohorts, ROSMAP and Mayo Clinic, sampling cerebral and cerebellum tissues from post-mortem human brain. Subsequentially, a drug repurposing strategy was utilized to identify cadidate compounds for modulating key pathways. While central co-expressed genes were investigated further to determine targetable genes as drug targets, standardised transcriptome profiles from cell culture experiments from Connectivity Map database were used to match the impact of target gene silencing and drug-inducement. Again using these profiles, candidate compounds were investigated computationally to determine their bioavailability and probable mechanisms of actions. in vitro examinations on glial cell line (U138MG) determined compound toxicity and efficacy levels.
While this research validated the prominence of lipids, vitamins and many other metabolites whose absence is detrimental to brain health, it also revealed several novel marker genes/proteins, i.e., AMIGO1 and GPRASP2, and marker metabolites, e.g., hexanoyl-CoA and pentanoyl-CoA, that were associated with AD for the first time. These findings emphasised the critical role of synaptic activity and energy metabolism in disease progression, particularly the dysregulation of glutamate metabolism. Subsequentially, high glutaminase expression was evaluated as a key contributor to glutamate excitotoxicity in AD. Using a profile-based drug repositioning method, novel compounds (e.g., SA-25547) and well-known compounds (e.g., parbendazole and bortezomib) were re-purposed for suppressing glutaminase activity and stabilising glutamate levels. Additional computational investigations and in vitro examinations illuminated the possible impact of drug actions on biological systems and evidenced drug efficacy on models, respectively. Re-visiting literature clarified the extended importance of glutamate metabolism in AD-linked events, including TCA cycle, neurotransmission and inflammatory response. Moreover, it was indicated that marker molecules can be leveraged to trace glutamate levels, thus, AD progression.
In summary, the work highlighted the central role of glutamate metabolism in AD pathology and demonstrated that its modulation stands as a viable therapeutic target. The identification of novel genetic and metabolic markers becomes a foundation for future diagnostic and therapeutic strategies. These findings highlighted the potential of systems medicine at disentangling the complexity of AD.
| Date of Award | 1 Nov 2024 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Adil Mardinoglu (Supervisor) & Saeed Shoaie (Supervisor) |