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Endogenous Apolipoprotein E4 modulates a sporadic Alzheimer’s disease phenotype in human stem-cell derived neurons

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The apolipoprotein E (APOE) E4 isoform is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). While APOE is predominantly expressed by astrocytes in the central nervous system, neuronal expression of APOE is of increasing interest in age-related cognitive impairment, neurological injury, and neurodegeneration. Here we show that endogenous expression of E4 in stem-cell derived neurons predisposes them to injury and promotes the release of phosphorylated tau. Induced pluripotent stem cells from two unrelated Alzheimer’s disease patients carrying the E4 allele were corrected to the E3/E3 genotype with the CRISPR/Cas9 system and differentiated into pure cultures of forebrain excitatory neurons without contamination from other cells types. Compared to unedited E4 neurons, E3 neurons were less susceptible to ionomycin-induced cytotoxicity. Biochemically, E4 cells exhibited increased tau phosphorylation and ERK1/2 phosphoactivation. Moreover, E4 neurons released increased amounts of phosphorylated tau extracellularly in an isoform dependent manner by a heparin sulfate proteoglycan-dependent mechanism. Our results demonstrate that endogenous expression of E4 by stem-cell derived forebrain excitatory neurons predisposes neurons to calcium dysregulation, and ultimately, cell death. This change is associated with increased cellular tau phosphorylation and markedly enhanced release of phosphorylated tau. Importantly, these effects are independent of glial APOE. These findings suggest that E4 accelerates spreading of tau pathology and neuron death in part by neuron-specific, glia-independent mechanisms.

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