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Investigating the Late-Alzheimer’s disease phenotype of CD2AP genetic risk in induced human neurons
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Orientador(es)
Resumo(s)
CD2-associated protein (CD2AP) is a genetic risk factor for Alzheimer’s disease (AD) and plays a critical
role in the production of amyloid-β (Aβ) and synaptic dysfunction, which are key early cellular indicators
of AD. However, how these mechanisms translate to human disease is still not understood.
One goal of this thesis was to generate a cellular model of synaptically mature human neurons. To address
this, we utilized human induced pluripotent stem cells (iPSCs) to develop a protocol for rapid neuronal
differentiation by overexpression of Neurogenin 2 (NGN2). The resulting induced neurons (iNeurons)
exhibited synaptic maturity and were evaluated for their potential to study APP trafficking in a human
neuronal context. This model provides a new platform to investigate the role of CD2AP in synaptic
dysfunction and APP processing in human neurons.
Another goal was to investigate whether CD2AP controls the spread of disease through intercellular
communication. CD2AP has been linked to endosomal maturation and the formation of intraluminal
vesicles, which are precursors of exosomes, a specialized group of extracellular vesicles (EVs) that may
spread APP toxic metabolites from affected neurons to unaffected ones. We examined how CD2AP may
influence exosome formation by isolating EVs from primary neurons and confirming their identity as
exosomes. When we knocked down CD2AP, we discovered increased levels of APP C-terminal fragments
in our EVs. This indicates that CD2AP may affect the composition or release of neuronal EVs. While these
findings are preliminary, they suggest a potential connection between CD2AP and disease spread through
exosomes, possibly revealing a new role for CD2AP in Alzheimer's disease.
This thesis laid the groundwork for studying the AD risk gene CD2AP in a human neuronal model that
produces synaptically mature neurons exhibiting APP-relevant localization to endosomes and processing.
Additionally, we gathered preliminary data suggesting CD2AP’s influence on exosome biology.
Descrição
Tese de mestrado, Bioqímica e Biomedicina, 2024, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
iPSC neurónios humanos CD2AP exosomas doença de azlheimer de início tardio Teses de mestrado - 2024