In vitro characterization on the role of APOE polymorphism in human hippocampal neurogenesis

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 epsilon 4 genotype is associated with a significantly earlier disease onset compared to the neutral epsilon 3 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 epsilon 4 at the stem cell stage, while the divergence of differential gene expression phenotype between epsilon 4 and epsilon 3 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 epsilon 4 and epsilon 3. Transcriptomic profiling across different stages of neurogenesis indicated a clear maturation of functional neurons phenotype in epsilon 3 neural progenitors and neurons, while genes differentially expressed only in epsilon 4 neurons suggested potential alterations in metabolism and mitochondrial function. Taken together, our in vitro investigation suggests that APOE epsilon 4 allele can exert a transcriptome-wide effect at the later stages of HN, without altering the overall level of neurogenesis per se.

Automated summary

Hippocampal neurogenesis (HN) is an important mechanism for brain plasticity and its alteration is linked to early Alzheimer's disease. APOE is a common genetic risk factor for late-onset Alzheimer's, and this study explores its impact on HN. Using an in vitro model, researchers found that APOE epsilon 4 allele affects gene expression and potentially metabolism and mitochondrial function during later stages of HN. However, it does not significantly alter the overall level of neurogenesis.