Amyloid beta accumulations and enhanced neuronal differentiation in cerebral organoids of Dutch-type cerebral amyloid angiopathy patients

Daoutsali, E.; Pepers, B.A.; Stamatakis, S.; Graaf, L.M. van der; Terwindt, G.M.; Parfitt, D.A.; Buijsen, R.A.M.; Roon-Mom, W.M.C. van

doi:doi:10.3389/fnagi.2022.1048584

Introduction: ADutch-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 (A beta) domain of APP and leads to A beta 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.Methods: We 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).Results: D-CAA cerebral organoids exhibited A beta accumulations, showed enhanced neuronal and astrocytic gene expression and TGF beta pathway de-regulation...Show moreIntroduction: ADutch-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 (A beta) domain of APP and leads to A beta 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.Methods: We 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).Results: D-CAA cerebral organoids exhibited A beta accumulations, showed enhanced neuronal and astrocytic gene expression and TGF beta pathway de-regulation.Conclusions: These 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 A beta-related disorders.Show less

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Amyloid beta accumulations and enhanced neuronal differentiation in cerebral organoids of Dutch-type cerebral amyloid angiopathy patients