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

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Resumo:Alzheimer’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.
Autores principais:Araújo, Margarida Nóbrega Campos de Freitas
Assunto:doença de Alzheimer de início tardio sinapses amiloide-β proteína precursora do amiloide tráfego Teses de mestrado - 2020
Ano:2020
País:Portugal
Tipo de documento:dissertação de mestrado
Tipo de acesso:acesso aberto
Instituição associada:Universidade de Lisboa
Idioma:inglês
Origem:Repositório da Universidade de Lisboa

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