Cerebral organoids derived from patients with Alzheimer’s disease with PSEN1/2 mutations have defective tissue patterning and altered development
Tereza Vanova,
Jiri Sedmik,
Jan Raska,
Katerina Amruz Cerna,
Petr Taus,
Veronika Pospisilova,
Marketa Nezvedova,
Veronika Fedorova,
Sona Kadakova,
Hana Klimova,
Michaela Capandova,
Petra Orviska,
Petr Fojtik,
Simona Bartova,
Karla Plevova,
Zdenek Spacil,
Hana Hribkova,
Dasa Bohaciakova
Affiliations
Tereza Vanova
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic; International Clinical Research Center (ICRC), St. Anne’s University Hospital, 60200 Brno, Czech Republic
Jiri Sedmik
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic
Jan Raska
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic; International Clinical Research Center (ICRC), St. Anne’s University Hospital, 60200 Brno, Czech Republic
Katerina Amruz Cerna
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic
Petr Taus
Central European Institute of Technology, Masaryk University, 62500 Brno, Czech Republic
Veronika Pospisilova
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic
Marketa Nezvedova
RECETOX, Faculty of Science, Masaryk University, 62500 Brno, Czech Republic
Veronika Fedorova
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic
Sona Kadakova
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic
Hana Klimova
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic
Michaela Capandova
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic
Petra Orviska
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic
Petr Fojtik
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic; International Clinical Research Center (ICRC), St. Anne’s University Hospital, 60200 Brno, Czech Republic
Simona Bartova
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic
Karla Plevova
Central European Institute of Technology, Masaryk University, 62500 Brno, Czech Republic; Institute of Medical Genetics and Genomics, University Hospital Brno and Faculty of Medicine, Masaryk University, 61300 Brno, Czech Republic
Zdenek Spacil
RECETOX, Faculty of Science, Masaryk University, 62500 Brno, Czech Republic
Hana Hribkova
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic
Dasa Bohaciakova
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic; International Clinical Research Center (ICRC), St. Anne’s University Hospital, 60200 Brno, Czech Republic; Corresponding author
Summary: During the past two decades, induced pluripotent stem cells (iPSCs) have been widely used to study human neural development and disease. Especially in the field of Alzheimer’s disease (AD), remarkable effort has been put into investigating molecular mechanisms behind this disease. Then, with the advent of 3D neuronal cultures and cerebral organoids (COs), several studies have demonstrated that this model can adequately mimic familial and sporadic AD. Therefore, we created an AD-CO model using iPSCs derived from patients with familial AD forms and explored early events and the progression of AD pathogenesis. Our study demonstrated that COs derived from three AD-iPSC lines with PSEN1(A246E) or PSEN2(N141I) mutations developed the AD-specific markers in vitro, yet they also uncover tissue patterning defects and altered development. These findings are complemented by single-cell sequencing data confirming this observation and uncovering that neurons in AD-COs likely differentiate prematurely.
