Early and lifelong effects of APOE4 on neuronal gene expression networks relevant to Alzheimer’s disease

Abstract

Apolipoprotein E4 (APOE4) genotype and aging are critical risk factors for Alzheimer’s disease (AD). Aged APOE4 knock-in (APOE4-KI) mice have phenotypes reflecting features of AD. We conducted a large-scale single nucleus RNA-sequencing study to identify cell-type-specific effects of APOE4 on hippocampal gene expression during aging. APOE4-KI mice showed prominent alterations, relative to APOE3-KI mice, in neuronal transcriptome related to synaptic function, calcium signaling, and MAPK/Rap1/Pld signal transduction, starting by 5 months and persisting during aging. Mice with the APOE4 gene removed specifically from neurons failed to show most of these neuronal transcriptomic changes, suggesting a specific effect of neuron-derived APOE4 on the transcriptome. APOE4 affects similar cellular pathways in induced pluripotent stem cell-derived human neurons transplanted into APOE4-KI mouse hippocampus and in cortical neurons from aged human brains. Thus, neuronal APOE4 has early and persistent effects on neuronal transcriptomes, suggesting the requirement of early interventions for successfully treating APOE4-related AD.

Phospholipase D1 Attenuation Therapeutics Promotes Resilience against Synaptotoxicity in 12-Month-Old 3xTg-AD Mouse Model of Progressive Neurodegeneration

“…Recent transcriptomic studies of human APOE3 and APOE4 knockin mice (APOE3-KI and APOE4-KI resp.) from 5 to 20 months of age show prominent changes in neuronal calcium signaling and synaptic function, implicating the phospholipase D (PLD) pathway [ 137 ]. APOE is the most abundant brain lipoprotein chaperones expressed mainly in astrocytes.…”