Neuronal Differentiation and Aβ Accumulations in Cerebral Organoids of D-CAA Patients

Published on January 17, 2023

Imagine you have a special kind of fruit tree, but instead of producing delicious fruit, it starts accumulating strange substances on its branches. This is similar to what happens in Dutch-type cerebral amyloid angiopathy (D-CAA), a brain disorder caused by a genetic mutation. Researchers generated miniature brain models called cerebral organoids from D-CAA patients and compared them to organoids from healthy individuals. They found that the D-CAA organoids displayed accumulations of amyloid beta (Aβ) peptides, which are involved in the disease. Additionally, these organoids showed a boost in the expression of genes related to neuron and astrocyte development, as well as deregulation in the TGFβ signaling pathway. These exciting findings highlight the potential of cerebral organoids as a valuable tool for studying D-CAA and other Aβ-related disorders. By using these organoids, scientists can delve deeper into the mechanisms behind D-CAA and potentially discover new therapeutic approaches. If you’re hungry for more knowledge about this fascinating research, be sure to check out the link below!

IntroductionADutch-type cerebral amyloid angiopathy (D-CAA) is a hereditary brain disorder caused by a point mutation in the amyloid precursor protein (APP) gene. The mutation is located within the amyloid beta (Aβ) domain of APP and leads to Aβ peptide accumulation in and around the cerebral vasculature. There lack of disease models to study the cellular and molecular pathological mechanisms of D-CAA together with the absence of a disease phenotype in vitro in overexpression cell models, as well as the limited availability of D-CAA animal models indicates the need for a D-CAA patient-derived model.MethodsWe generated cerebral organoids from four D-CAA patients and four controls, cultured them up to 110 days and performed immunofluorescent and targeted gene expression analyses at two time points (D52 and D110).ResultsD-CAA cerebral organoids exhibited Aβ accumulations, showed enhanced neuronal and astrocytic gene expression and TGFβ pathway de-regulation.ConclusionsThese results illustrate the potential of cerebral organoids as in vitro disease model of D-CAA that can be used to understand disease mechanisms of D-CAA and can serve as therapeutic intervention platform for various Aβ-related disorders.

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