Abstract: Apolipoprotein E has diverse functions in neurons: Apolipoprotein E (ApoE) is a glycoprotein that primarily regulates lipid metabolism and transport in the central nervous system. There are three predominant human ApoE protein isoforms with cysteine and arginine substitutions at amino acid positions 112 and 158 that impact their lipidation and related functions (Flowers and Rebeck, 2020). ApoE2 is characterized by Cys112 and Cys158, ApoE3 by Cys112 and Arg158, whereas ApoE4 contains Arg112 and Arg158. Among these genetic variants, ApoE4 allele is the strongest risk factor for late-onset sporadic Alzheimer’s disease whereas ApoE2 is linked to cardiovascular disease. ApoE is predominantly produced by astrocytes with lower levels detected in other cell types in the brain. While ApoE displayed strong immunoreactivity in astrocytes, its level in the neurons appeared to be affected by different pathological conditions. Higher ApoE level was detected in neurons surrounding ischemic foci in cerebral infarction or senile plaques from Alzheimer’s disease brains, suggesting that ApoE might participate in repair pathways following injuries (Aoki et al., 2003). In addition to lipid metabolism, several studies showed that ApoE may perform other molecular functions in the neurons. For instance, ApoE3 secreted by astrocytes vectored microRNAs (miRNAs) into neurons where they silenced cholesterol biosynthesis genes and facilitated H3K27ac-mediated activation of genes linked to memory consolidation (Li et al., 2021). Transcriptome profiling of neurons derived from human induced pluripotent stem cells also showed that ApoE3 and ApoE4 isoforms could elicit distinct genetic programs that are implicated in Alzheimer’s disease progression (Lin et al., 2018). In adult mouse dentate gyrus, ApoE suppressed the over-proliferation of neural stem cells (NSCs) to maintain the pool of neural progenitor cells (NPCs) (Yang et al., 2011). While these results highlight the diverse molecular roles played by ApoE in neurons, its regulatory mechanisms at different stages of neurogenesis remain elusive.