TY - JOUR
T1 - In vitro characterization on the role of APOE polymorphism in human hippocampal neurogenesis
AU - Thuret, Sandrine
AU - Lee, Hyunah
AU - Srivastava, Deepak
AU - Price, Jack
N1 - Funding Information:
PhD studentship of Hyunah Lee was sponsored by the King's College London Graduate School PGR (postgraduate research) International Research Studentship. Some of this work was funded by Medical Research Council (MRC) research grants awarded to Sandrine Thuret [MR/N030087/1 and MR/S00484X/1]. The authors would like to thank Dr Maria Carolina Marchetto for sharing the details of the in vitro differentiation protocol, Paulina Nowosiad for her guidance on cell culture and maintenance of pluripotent stem cells, and the Wohl Cellular Imaging Centre (WCIC). Hyunah Lee would like to express gratitude to Sebastian Dohm-Hansen Allard for sharing the gene set enrichment analysis protocol, and Dr Graham Cocks for the insightful discussion on APOE expression in neural stem cells.
Funding Information:
PhD studentship of Hyunah Lee was sponsored by the King's College London Graduate School PGR (postgraduate research) International Research Studentship. Some of this work was funded by Medical Research Council (MRC) research grants awarded to Sandrine Thuret [MR/N030087/1 and MR/S00484X/1]. The authors would like to thank Dr Maria Carolina Marchetto for sharing the details of the in vitro differentiation protocol, Paulina Nowosiad for her guidance on cell culture and maintenance of pluripotent stem cells, and the Wohl Cellular Imaging Centre (WCIC). Hyunah Lee would like to express gratitude to Sebastian Dohm‐Hansen Allard for sharing the gene set enrichment analysis protocol, and Dr Graham Cocks for the insightful discussion on expression in neural stem cells. APOE
Publisher Copyright:
© 2023 The Authors. Hippocampus published by Wiley Periodicals LLC.
PY - 2023/4
Y1 - 2023/4
N2 - Hippocampal neurogenesis (HN) is considered an important mechanism underlying lifelong brain plasticity, and alterations in this process have been implicated in early Alzheimer's disease progression. APOE polymorphism is the most common genetic risk factor for late-onset Alzheimer's disease where the ε4 genotype is associated with a significantly earlier disease onset compared to the neutral ε3 allele. Recently, APOE has been shown to play an important role in the regulation of HN. However, the time-dependent impact of its polymorphism in humans remains elusive, partially due to the difficulties of studying human HN in vivo. To bridge this gap of knowledge, we used an in vitro cellular model of human HN and performed a time course characterization on isogenic induced pluripotent stem cells with different genotypes of APOE. We found that APOE itself was more highly expressed in ε4 at the stem cell stage, while the divergence of differential gene expression phenotype between ε4 and ε3 became prominent at the neuronal stage of differentiation. This divergence was not associated with the differential capacity to generate dentate gyrus granule cell-like neurons, as its level was comparable between ε4 and ε3. Transcriptomic profiling across different stages of neurogenesis indicated a clear “maturation of functional neurons” phenotype in ε3 neural progenitors and neurons, while genes differentially expressed only in ε4 neurons suggested potential alterations in “metabolism and mitochondrial function.” Taken together, our in vitro investigation suggests that APOE ε4 allele can exert a transcriptome-wide effect at the later stages of HN, without altering the overall level of neurogenesis per se.
AB - Hippocampal neurogenesis (HN) is considered an important mechanism underlying lifelong brain plasticity, and alterations in this process have been implicated in early Alzheimer's disease progression. APOE polymorphism is the most common genetic risk factor for late-onset Alzheimer's disease where the ε4 genotype is associated with a significantly earlier disease onset compared to the neutral ε3 allele. Recently, APOE has been shown to play an important role in the regulation of HN. However, the time-dependent impact of its polymorphism in humans remains elusive, partially due to the difficulties of studying human HN in vivo. To bridge this gap of knowledge, we used an in vitro cellular model of human HN and performed a time course characterization on isogenic induced pluripotent stem cells with different genotypes of APOE. We found that APOE itself was more highly expressed in ε4 at the stem cell stage, while the divergence of differential gene expression phenotype between ε4 and ε3 became prominent at the neuronal stage of differentiation. This divergence was not associated with the differential capacity to generate dentate gyrus granule cell-like neurons, as its level was comparable between ε4 and ε3. Transcriptomic profiling across different stages of neurogenesis indicated a clear “maturation of functional neurons” phenotype in ε3 neural progenitors and neurons, while genes differentially expressed only in ε4 neurons suggested potential alterations in “metabolism and mitochondrial function.” Taken together, our in vitro investigation suggests that APOE ε4 allele can exert a transcriptome-wide effect at the later stages of HN, without altering the overall level of neurogenesis per se.
UR - http://www.scopus.com/inward/record.url?scp=85147311074&partnerID=8YFLogxK
U2 - 10.1002/hipo.23502
DO - 10.1002/hipo.23502
M3 - Article
SN - 1050-9631
VL - 33
SP - 322
EP - 346
JO - Hippocampus
JF - Hippocampus
IS - 4
ER -
