Publicação
The signalling pathways of secretases in APP processing: an OMICS approach for neuronal health
| Resumo: | The Alzheimer’s Amyloid Precursor Protein (APP), a central protein in Alzheimer´s Disease (AD), is metabolized in a highly complex fashion by a series of sequential secretases, which can lead to α, β, and γ-cleavage, accordingly. The toxic abilities of the resulting fragments are a direct consequence of the first cleaving secretase: β-secretase (BACE1) induces an amyloid cleavage while, α-secretase (ADAM10 and ADAM17) cleavage does not have the same pathological impact in AD. The latter is currently being studied as a therapeutic target for preventing or reverting the initial biochemical events of AD, as it may compete with BACE1 for APP’s first cleavage. Literature demonstrates that retinoic acid (RA) receptor (RAR) alters secretase activity, suggesting anti-amyloid effects: downregulation of Amyloid-β-peptide (Aβ) releasing secretases (β and γ-secretase) and upregulation of the beneficial α-secretase. In addition, RA reduces neuroinflammation and promotes neurite growth. To experimentally verify the impact of RA, the SH-SY5Y neuronal cell line was used. Differentiated cells were treated for 48 hours with retinoids agonists and antagonists for different RAR isoforms. Treatments suggest alterations in proteins directly associated with AD, that can be either benefitial or pathlogical, depending the RAR isoform being stimulated. The APP secretaseome was compiled and analyzed. The data from a YTH system was introduced and new potential interactors described. Targets from a holistic and systems aproach were identified as potencial interest proteins for further understanding the impact of stimulating each RAR isoform. Data from mass spectophotometry analysis of the insoluble fraction of human fibroblasts from AD patients was also introduced in the search for targets in the holistic and systems medicine perspective. Coincidentelly, some targets were found in common when compared with the APP secretase network, being possible important proteins in the context of AD neurodegeneration pathways. In conclusion, bioinformatic approaches provide global and dynamic results on molecular changes and interactions under different conditions, of particular interest for complex pathologies such as AD. Induced therapeutic changes must restore homeostasis and not only alter the specific source of the problem. The combination of bioinformatics and wet lab tools provides a putative gateway, with promising results in the specific study of effects resulting from the stimulattion of the retinoid acid receptor as a potential therapy for AD. |
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| Autores principais: | Vitória, José João Mendonça |
| Assunto: | α-secretases β-secretases ϒ-secretases Retinoic acid Amyloid-beta precursor protein APP secretaseome network APP processing Amyloid-β peptide Alzheimer´s disease Neurodegeneration |
| Ano: | 2021 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Aveiro |
| Idioma: | inglês |
| Origem: | RIA - Repositório Institucional da Universidade de Aveiro |
| Resumo: | The Alzheimer’s Amyloid Precursor Protein (APP), a central protein in Alzheimer´s Disease (AD), is metabolized in a highly complex fashion by a series of sequential secretases, which can lead to α, β, and γ-cleavage, accordingly. The toxic abilities of the resulting fragments are a direct consequence of the first cleaving secretase: β-secretase (BACE1) induces an amyloid cleavage while, α-secretase (ADAM10 and ADAM17) cleavage does not have the same pathological impact in AD. The latter is currently being studied as a therapeutic target for preventing or reverting the initial biochemical events of AD, as it may compete with BACE1 for APP’s first cleavage. Literature demonstrates that retinoic acid (RA) receptor (RAR) alters secretase activity, suggesting anti-amyloid effects: downregulation of Amyloid-β-peptide (Aβ) releasing secretases (β and γ-secretase) and upregulation of the beneficial α-secretase. In addition, RA reduces neuroinflammation and promotes neurite growth. To experimentally verify the impact of RA, the SH-SY5Y neuronal cell line was used. Differentiated cells were treated for 48 hours with retinoids agonists and antagonists for different RAR isoforms. Treatments suggest alterations in proteins directly associated with AD, that can be either benefitial or pathlogical, depending the RAR isoform being stimulated. The APP secretaseome was compiled and analyzed. The data from a YTH system was introduced and new potential interactors described. Targets from a holistic and systems aproach were identified as potencial interest proteins for further understanding the impact of stimulating each RAR isoform. Data from mass spectophotometry analysis of the insoluble fraction of human fibroblasts from AD patients was also introduced in the search for targets in the holistic and systems medicine perspective. Coincidentelly, some targets were found in common when compared with the APP secretase network, being possible important proteins in the context of AD neurodegeneration pathways. In conclusion, bioinformatic approaches provide global and dynamic results on molecular changes and interactions under different conditions, of particular interest for complex pathologies such as AD. Induced therapeutic changes must restore homeostasis and not only alter the specific source of the problem. The combination of bioinformatics and wet lab tools provides a putative gateway, with promising results in the specific study of effects resulting from the stimulattion of the retinoid acid receptor as a potential therapy for AD. |
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