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Bioinformatics investigation of the amyloid precursor protein and its interactions with presenilin-1 and acetylcholinesterase in early onset familial Alzheimer's disease / JOIC JACINTO

Swansea University Author: JOIC JACINTO

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Abstract

Since the discovery of the amyloid precursor protein (APP) over 30 years ago, scientists have investigated its involvement in Alzheimer's disease (AD). They have also found specific cases where mutations in this gene led to the early onset familial form of AD (EOFAD). However, little attention h...

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Published: Swansea University 2026
Institution: Swansea University
Degree level: Master of Research
Degree name: MSc by Research
URI: https://cronfa.swan.ac.uk/Record/cronfa71439
Abstract: Since the discovery of the amyloid precursor protein (APP) over 30 years ago, scientists have investigated its involvement in Alzheimer's disease (AD). They have also found specific cases where mutations in this gene led to the early onset familial form of AD (EOFAD). However, little attention has been paid to the structural mechanisms by which these EOFAD mutations trigger AD pathogenesis, probably due to the relatively small percentage of AD patients (<1%) that carry these missense mutations. By using bioinformatics tools (i.e. STRING, Reactome, UCSF Chimera, AlphaFold2, AlphaFold Server) and databases (i.e. ClinVar, UniProt, PDB), APP and the pathological consequences of EOFAD mutations were studied comprehensively. By exploring the network of proteins that APP physically or functionally interacts with, key interactors were identified. Presenilin-1 (PSEN1) is one of them. PSEN1 is part of the γ-secretase complex, involved in the amyloidogenic processing of APP, leading to the formation of Aβ peptides. Another interactor is the enzyme acetylcholinesterase (ACHE).Their interaction is less known, but they have been found to co-localise in neurons. ACHE is responsible for the hydrolysis and recycling of the neurotransmitter acetylcholine.Investigating the APP-PSEN1 and APP-ACHE complexes at the molecular level provides opportunities for identification of key binding amino acids – valuable information for understanding pathological mechanisms and discovering novel drug targets. In the context of EOFAD, some of these APP mutations might be closely involved with such amino acids or might influence important structural regions involved in their protein-protein interface.These findings highlight the importance of further investigating the structural intricacies of APP and its interactions, offering new avenues for understanding EOFAD pathogenesis and identifying potential therapeutic targets that could benefit both rare and common forms of AD.
Keywords: Bioinformatics, Alzheimer&apos;s disease, protein structures, missense variants, APP
College: Faculty of Medicine, Health and Life Sciences

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