Author: Mousa Alghazwi
Alghazwi, Mousa, 2018 Discovery of potential neuroprotective compounds from marine sponges and algae, Flinders University, College of Medicine and Public Health
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Alzheimer’s disease (AD) is the major neurodegenerative disease responsible for more than 60% of dementia cases globally. One of the main hallmarks of AD is the presence of amyloid beta (Aβ) protein that forms plaques in the brain. Aβ1-40 and Aβ1-42 are two major forms generated from the cleavage of amyloid precursor protein (APP) by β-secretase and γ-secretase. Current treatment strategies for AD mostly target acetylcholinesterase and the N-methyl-D-aspartate (NMDA) receptor. However, these treatments can only mitigate some of the cognitive and memory loss symptoms and are not considered disease-modifying. Hence, the development of new treatments for AD is required. This study aimed to find new neuroprotective compounds from marine sponges and algae with bioactivity against the neurotoxicity and aggregation of Aβ1-42.
Ninety-two extracts from marine sponges and algae (43, 13, 16, and 20 extracts from sponge, green algae, brown algae, and red algae, respectively) from South Australia have been screened initially for neurotoxicity. Only extracts that did not show cytotoxicity (45) were used for further study to characterise their bioactivity against the cytotoxicity induced by Aβ1-42. This study showed that one-third of 92 extracts screened (29) were found to reduce neurotoxicity induced by Aβ1-42 in PC-12 cells. In silico modelling was also used to screen the potential of compounds isolated from marine sponges and algae that showed activities in reducing the aggregation propensity of Aβ1-42. Astaxanthin and fucoxanthin were selected as promising compounds due to their high docking scores to Aβ1-42 and their commercial availability. It was subsequently demonstrated that both compounds inhibited the cytotoxicity induced by both Aβ1-42 and hydrogen peroxide. In addition, these compounds demonstrated anti-aggregation effects in the Thioflavin T (ThT) assay for inhibition of Aβ1-42 fibrillisation kinetics and via transmission electron microscopy (TEM) for morphological alteration of fibrils and aggregates. Molecular docking studies of the binding of these compounds were also performed in order to find the optimal binding regions of these compounds with Aβ1-42. Furthermore, these compounds were shown to inhibit the apoptosis induced by Aβ1-42, and also to enhance neurite outgrowth activity.
To explore the potential of South Australia-algae-derived functional food and nutrient manipulation for neuroprotection, six different fractions of the brown macroalgae Ecklonia radiata and five fucoidan samples have been studied for their neuroprotective potential. These samples were screened for their neuroprotective activities against the cytotoxicity and aggregation of Aβ1-42; antioxidant activity in reducing the cytotoxicity induced by hydrogen peroxide and apoptosis induced by Aβ1-42; and neurite outgrowth activity. The results showed that these samples have different neuroprotective activities and impacts on neurite outgrowth. The fractionation process has significant impact on neuroprotective activities of the fraction samples produced, highlighting the significance of process development on bioactivities. In general, astaxanthin and fucoxanthin demonstrated the highest neuroprotective activities among other compounds/extracts used in this study with significant results (one way ANOVA) in all assays.
Overall, this project has demonstrated great potential of marine sponges, especially algae as sources of neuroprotective compounds in both functional food and pharmaceutical applications toward modifying and alleviating neurodegenerative diseases.
Keywords: Marine sponges, macroalgae, seaweed, neuroprotective activity, amyloid beta, South Australia, Ecklonia radiata, Alzheimer’s disease, fucoidan, astaxanthin, fucoxanthin, biotechnology
Subject: Medical Biotechnology thesis
Thesis type: Doctor of Philosophy
Completed: 2018
School: College of Medicine and Public Health
Supervisor: Prof Wei Zhang