Investigating the mechanisms of synaptic dysfunction in late-onset Alzheimer’s disease

Bibliographic Details
Main Author: Araújo, Margarida Nóbrega Campos de Freitas
Publication Date: 2020
Format: Master thesis
Language: eng
Source: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
Download full: http://hdl.handle.net/10451/48747
Summary: Tese de mestrado, Biologia Molecular e Genética, Universidade de Lisboa, Faculdade de Ciências, 2020
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spelling Investigating the mechanisms of synaptic dysfunction in late-onset Alzheimer’s diseasedoença de Alzheimer de início tardiosinapsesamiloide-βproteína precursora do amiloidetráfegoTeses de mestrado - 2020Departamento de Biologia VegetalTese de mestrado, Biologia Molecular e Genética, Universidade de Lisboa, Faculdade de Ciências, 2020Alzheimer’s disease (AD) is the most common neurodegenerative disorder, characterized by progressive memory loss. Amyloid-β (Aβ) accumulation plays a central role in AD and is associated with progressive synaptic dysfunction and neuronal death. Aβ is produced by sequential cleavage of the amyloid precursor protein (APP) by beta-site APP-cleaving enzyme 1 (BACE1) and γ-secretase at the early endosomal membrane. Differential trafficking of APP and BACE1 to early endosomes controls Aβ production. Late-onset AD (LOAD) represents 99 % of AD cases. The cause of LOAD is still largely unknown, but evidence points towards a combination of ageing, lifestyle, and genetic risk factors. CD2- associated protein (CD2AP), is a putative LOAD genetic risk factor, implicated in APP intracellular trafficking. This work focused on investigating the molecular mechanisms by which a LOAD CD2AP variant, rs116754410, that introduces a mutation on CD2AP, interferes with Aβ production through APP trafficking regulation. Using the Neuro-2-a cell line and primary mouse neurons, and immunofluorescence and immunoblotting methods, we found that overexpression of the CD2AP mutation, more than CD2AP wild-type, increases intracellular Aβ42, the most toxic Aβ species, in dendritic spines. We determined that wild-type CD2AP increases the sorting of APP from the early- and late-endosomal membrane for degradation. The mutant CD2AP instead leads to the accumulation of APP at the endosomal membrane, hindering its lysosomal degradation. In conclusion, the CD2AP LOAD mutation may increase Aβ accumulation by retaining APP at the membrane of endosomal compartments, potentiating its processing by BACE1 and γ-secretase. Since this Aβ accumulation happens preferentially in dendritic spines, it may impact local synaptic transmission. Thus, genetic variants in CD2AP may contribute to triggering AD pathogenesis.Almeida, Cláudia Guimas de, 1976-Reis, Diana Lina Jerónimo da Cunha, 1973-Repositório da Universidade de LisboaAraújo, Margarida Nóbrega Campos de Freitas2023-12-27T01:32:47Z202020202020-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10451/48747TID:202695328enginfo:eu-repo/semantics/openAccessreponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiainstacron:RCAAP2025-03-17T14:35:21Zoai:repositorio.ulisboa.pt:10451/48747Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireinfo@rcaap.ptopendoar:https://opendoar.ac.uk/repository/71602025-05-29T03:16:28.350890Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiafalse
dc.title.none.fl_str_mv Investigating the mechanisms of synaptic dysfunction in late-onset Alzheimer’s disease
title Investigating the mechanisms of synaptic dysfunction in late-onset Alzheimer’s disease
spellingShingle Investigating the mechanisms of synaptic dysfunction in late-onset Alzheimer’s disease
Araújo, Margarida Nóbrega Campos de Freitas
doença de Alzheimer de início tardio
sinapses
amiloide-β
proteína precursora do amiloide
tráfego
Teses de mestrado - 2020
Departamento de Biologia Vegetal
title_short Investigating the mechanisms of synaptic dysfunction in late-onset Alzheimer’s disease
title_full Investigating the mechanisms of synaptic dysfunction in late-onset Alzheimer’s disease
title_fullStr Investigating the mechanisms of synaptic dysfunction in late-onset Alzheimer’s disease
title_full_unstemmed Investigating the mechanisms of synaptic dysfunction in late-onset Alzheimer’s disease
title_sort Investigating the mechanisms of synaptic dysfunction in late-onset Alzheimer’s disease
author Araújo, Margarida Nóbrega Campos de Freitas
author_facet Araújo, Margarida Nóbrega Campos de Freitas
author_role author
dc.contributor.none.fl_str_mv Almeida, Cláudia Guimas de, 1976-
Reis, Diana Lina Jerónimo da Cunha, 1973-
Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Araújo, Margarida Nóbrega Campos de Freitas
dc.subject.por.fl_str_mv doença de Alzheimer de início tardio
sinapses
amiloide-β
proteína precursora do amiloide
tráfego
Teses de mestrado - 2020
Departamento de Biologia Vegetal
topic doença de Alzheimer de início tardio
sinapses
amiloide-β
proteína precursora do amiloide
tráfego
Teses de mestrado - 2020
Departamento de Biologia Vegetal
description Tese de mestrado, Biologia Molecular e Genética, Universidade de Lisboa, Faculdade de Ciências, 2020
publishDate 2020
dc.date.none.fl_str_mv 2020
2020
2020-01-01T00:00:00Z
2023-12-27T01:32:47Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/masterThesis
format masterThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/48747
TID:202695328
url http://hdl.handle.net/10451/48747
identifier_str_mv TID:202695328
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron:RCAAP
instname_str FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron_str RCAAP
institution RCAAP
reponame_str Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
collection Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
repository.name.fl_str_mv Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
repository.mail.fl_str_mv info@rcaap.pt
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