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Targeting mitochondria of neural stem cells for neuroregeneration

2019-10Tese de doutoramento Acesso aberto
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datacite.subject.fosCiências Médicas::Medicina Básicapt_PT
dc.contributor.advisorCruz, Susana Zeferino Solá da
dc.contributor.advisorRodrigues, Cecília Maria Pereira
dc.contributor.authorRibeiro, Maria Filipe Canas de Matos e Oliveira
dc.date.accessioned2020-02-12T10:29:00Z
dc.date.available2022-10-01T00:30:49Z
dc.date.issued2019-10
dc.date.submitted2019-07
dc.description.abstractThe adult mammalian brains display the capacity to generate new neurons from existing neural stem cells (NSCs) in a process called adult neurogenesis. This process drops sharply throughout ageing and is further impaired in neurodegenerative diseases and other neurological disorders. Curiously, mitochondria and mitochondrial metabolism have been shown to be key regulators of NSC fate. The influence of factors such as ageing, metabolism and diet on brain function is also becoming increasingly recognised. Interestingly, emerging data have supported a crosstalk between the brain and gut microbiota, through the modulation of host metabolism. In the present project, we aimed to dissect the molecular mitochondrial mechanisms responsible for neurogenesis alterations in the context of both neurodegeneration, such as in Alzheimer’s disease (AD), and dietary challenge. Initially, we investigated the impact of amyloid-β (Aβ) peptide, a hallmark of AD, in NSC fate and explored the contribution of mitochondria for Aβ-induced NSC changes. We showed that high levels of Aβ peptide result in mitochondrial signalling disruption, affecting NSC viability, proliferation and differentiation. Importantly, under elevated amyloid burden, an irreversible dysfunction of mitochondrial biogenesis, dynamics and oxidative state was found, precluding any rescue of neurogenesis through mitochondria. We then explored the role of mitochondrial signalling pathways in mediating the regulation of adult neurogenesis following a dietary challenge and subsequent changes in diet-associated gut microbiota. Interestingly, we discovered that animals fed a high-fat choline deficient diet (HFCD) diet display premature increased neurogenesis, which further exhausts the NSC pool for long-term neurogenesis. In fact, HFCD diet stimulated gut dysbiosis, upregulating metabolic pathways of short chain fatty acids (SCFAs), such as propionate and butyrate, in the small intestine and cecum. More importantly, the microbial metabolites enhanced mitochondrial biogenesis and oxidative stress in NSCs, while also promoting early neuronal differentiation through a ROS- and p-ERK1/2-dependent mechanism. Notably, this mitochondrial stressdependent pathway was activated in neurogenic niches of HFCD diet-fed mice. In conclusion, our findings clarify the impact of mitochondrial activity during adult neurogenesis and may prove useful in the development of novel strategies to rescue adult neurogenesis.pt_PT
dc.description.provenanceSubmitted by Paula Guerreiro (passarinho@reitoria.ulisboa.pt) on 2020-02-04T15:03:01Z No. of bitstreams: 1 ULSD734071_td_Maria_Ribeiro.pdf: 33988644 bytes, checksum: 8e2a26ecbb03251fce9a3716b74554fe (MD5)en
dc.description.provenanceMade available in DSpace on 2020-02-12T10:29:00Z (GMT). No. of bitstreams: 1 ULSD734071_td_Maria_Ribeiro.pdf: 33988644 bytes, checksum: 8e2a26ecbb03251fce9a3716b74554fe (MD5) Previous issue date: 2019-10en
dc.identifier.tid101512180pt_PT
dc.identifier.urihttp://hdl.handle.net/10451/41763
dc.language.isoengpt_PT
dc.relationLISBOA-01-0145-FEDER-016405pt_PT
dc.relationPROBING AND TARGETING MITOCHONDRIA BIOENERGETICS IN NEURODEGENERATION
dc.relationMetabolic Control of Neural Repair by Diet and Gut Microbiome during Aging
dc.relationResearch Institute for Medicines
dc.relationPRECISION ONCOLOGY BY INNOVATIVE THERAPIES AND TECHNOLOGIES
dc.subjectAmyloid-β peptidept_PT
dc.subjectMicrobiotapt_PT
dc.subjectMitochondriapt_PT
dc.subjectNeurogenesispt_PT
dc.subjectShort chain fatty acidspt_PT
dc.titleTargeting mitochondria of neural stem cells for neuroregenerationpt_PT
dc.typedoctoral thesis
dspace.entity.typePublication
oaire.awardNumberSFRH/BD/100674/2014
oaire.awardNumberUID/DTP/04138/2013
oaire.awardNumberPTDC/MED-NEU/29650/2017
oaire.awardNumberUID/DTP/04138/2019
oaire.awardNumberSAICTPAC/0019/2015
oaire.awardTitlePROBING AND TARGETING MITOCHONDRIA BIOENERGETICS IN NEURODEGENERATION
oaire.awardTitleMetabolic Control of Neural Repair by Diet and Gut Microbiome during Aging
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitlePRECISION ONCOLOGY BY INNOVATIVE THERAPIES AND TECHNOLOGIES
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F100674%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FDTP%2F04138%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FMED-NEU%2F29650%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FDTP%2F04138%2F2019/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/9471 - RIDTI/SAICTPAC%2F0019%2F2015/PT
oaire.fundingStreamOE
oaire.fundingStream5876
oaire.fundingStream3599-PPCDT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream9471 - RIDTI
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typedoctoralThesispt_PT
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relation.isProjectOfPublication3ea9d46e-a653-42ed-aa04-6630ede070cc
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thesis.degree.nameTese de doutoramento, Farmácia (Biologia Celular e Molecular), Universidade de Lisboa, Faculdade de Farmácia, 2019pt_PT

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