Chulalongkorn University Theses and Dissertations (Chula ETD)
Other Title (Parallel Title in Other Language of ETD)
ฤทธิ์ในการป้องกันความเสื่อมของเซลล์ประสาทของสารสกัดเสาวรสจากความเป็นพิษที่ถูกกระตุ้นด้วยอะไมลอยด์เบต้า
Year (A.D.)
2021
Document Type
Thesis
First Advisor
Tewin Tencomnao
Second Advisor
Evandro Fei Fang
Faculty/College
Faculty of Allied Health Sciences (คณะสหเวชศาสตร์)
Department (if any)
Department of Clinical Chemistry (ภาควิชาเคมีคลินิก)
Degree Name
Doctor of Philosophy
Degree Level
Doctoral Degree
Degree Discipline
Clinical Biochemistry and Molecular Medicine
DOI
10.58837/CHULA.THE.2021.1282
Abstract
Alzheimer’s disease (AD) is a common and devastating disease characterized by pathological aggregations of beta-amyloid (Aβ) plaques extracellularly, and Tau tangles intracellularly. While our understandings of the aetiologies of AD have greatly expanded over the decades, there is no drug available to stop disease progression. This study involves two parts. First, we demonstrate the potential of P. edulis pericarp (PP) extract in protecting against Aβ-mediated neurotoxicity in mammalian cells and Caenorhabditis elegans models of AD. We show PP protects against memory deficit, neuronal loss, and promotes longevity in the Aβ model of AD via stimulation of mitophagy, the selective cellular clearance of damaged and dysfunctional mitochondria. PP also restores memory and increases neuronal resilience in a C. elegans Tau model of AD. While the defective mitophagy-induced accumulation of damaged mitochondria contributes to AD progression, PP improves mitochondrial homeostasis through NIX/DCT1-dependent mitophagy and SOD3-dependent mitochondrial resilience, both via increased nuclear translocation of the upstream transcriptional regulator FOXO3/DAF-16. The data suggest that the active molecules in PP that could maintain neuronal mitochondrial homeostasis may enable the development of potential drug candidates for AD. Based on the literature review and the in silico results, the second part of this study is carried out using α(β)- Amyrin. According to the Braak staging of AD, the formation of Tau aggregates starts from the entorhinal cortex, eventually spreading to the neocortex, likely due to increased Tau production, transmission and seed aggregation of soluble Tau and reduced Tau clearance. Autophagy (including the selective sub-type mitophagy), a cellular process with self-recognition and degradation of subcellular components, plays a pivotal role in the clearance of protein aggregates, and is compromised in AD. Here we report the identification of α-Amyrin, a natural pentacyclic triterpenol, as a robust neuronal mitophagy inducer to inhibit Tau pathologies. α-Amyrin specifically upregulates the key autophagy gene ULK1/unc51 and activates ULK1 by phosphorylating Ser555 and inhibiting Ser757. α-Amyrin abrogates Tau pathologies as it inhibits exogenous recombinant heparin-assembled P301S (Tau assemblies)-induced endogenous Tau aggregation and promotes degradation of endogenous Tau aggregates. Furthermore, α-Amyrin inhibits memory deficits in P301L-Tau nematodes in a ULK1/unc51-dependent manner. α-Amyrin also improves the resilience of cholinergic and glutamatergic neurons which are fragile and dysfunctional in AD. Our findings are supported by similar data generated by its counterpart β-Amyrin, which shares a very similar structure to α-Amyrin. Collectively, α- and β-Amyrins inhibit Tau pathologies via upregulation of ULK1/UNC-51-dependent mitophagy/autophagy, holding translational potential against AD.
Other Abstract (Other language abstract of ETD)
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Creative Commons License
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Recommended Citation
Cao, Shuqin, "Neuroprotective effect of passiflora edulissims against amyloid beta-induced neurotoxicity" (2021). Chulalongkorn University Theses and Dissertations (Chula ETD). 12442.
https://digital.car.chula.ac.th/chulaetd/12442