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In Vivo Chimeric Alzheimer’s Disease Modeling of Apolipoprotein E4 Toxicity in Human Neurons

ABSTRACT: Despite its clear impact on Alzheimer’s Disease (AD) risk, apolipoprotein (apo) E4’s contributions to AD etiology remain poorly understood. Progress in answering this and other questions in AD research has been limited by an inability to model human-specific phenotypes in an in vivo environment. Here we transplanted human induced pluripotent stem cell (hiPSC)-derived neurons carrying normal apoE3 or pathogenic apoE4 into human apoE3 or apoE4 knock-in mouse hippocampi, enabling us to disentangle the effects of apoE4 produced in human neurons and in the brain environment. Using single nucleus RNA-sequencing (snRNA-seq), we identified key transcriptional changes specific to human neuron subtypes in response to endogenous or exogenous apoE4. We also found that Aβ from transplanted human neurons formed plaque-like aggregates, with differences in localization and interaction with microglia depending on the transplant and host apoE genotype. These findings highlight the power of in vivo chimeric disease modeling for studying AD.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE152867 | GEO | 2020/06/20

REPOSITORIES: GEO

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Project description:The APOE gene is diversified by three alleles e2, e3, and e4 encoding corresponding apolipoprotein (apo) E isoforms. The e4 allele promotes age-related cognitive decline, risk of Alzheimer’s disease (AD), and the rate of AD dementia progression. ApoE is produced by astrocytes as high-density lipoprotein-like particles and these are internalized by neurons upon binding to neuron-expressed apoE receptors. ApoE isoforms differentially engage neuronal plasticity through poorly understood mechanisms. We examined here the effects of native apoE lipoproteins produced by immortalized astrocytes homozygous for e2, e3, and e4 alleles on the maturation and the transcriptomic profile of primary hippocampal neurons. Control neurons were grown in the presence of conditioned media from Apoe-/- astrocytes. ApoE2 and apoE3 significantly increase the dendritic arbor branching, the combined neurite length, and the total arbor surface of the hippocampal neurons, while apoE4 fails to produce similar effects and even significantly reduces the combined neurite length compared to the control. ApoE lipoproteins show no systemic effect on dendritic spine density, yet apoE2 and apoE3 increase the mature spines fraction, while apoE4 increases the immature spine fraction. This is associated with opposing effects of apoE2 or apoE3 and apoE4 on the expression of NR1 NMDA receptor subunit and PSD95. There are 1,062 genes differentially expressed across neurons cultured in the presence of apoE lipoproteins compared to the control. KEGG enrichment and gene ontology analyses show common for apoE2 and apoE3 activation of genes involved in neurite branching, and synaptic signaling. In contrast, apoE4 cultured neurons show upregulation of genes related to the glycolipid metabolism, which are involved in dendritic spine turnover and those which are usually silent in neurons and are related to cell cycle and DNA repair. In conclusion our work reveals that lipoprotein particles comprised of various apoE isoforms differentially regulate neuronal development through interaction with neuronal transcriptome. ApoE4 produces a functionally distinct transcriptomic profile, which is associated with attenuated neuronal development. Differential regulation of neuronal transcriptome by apoE isoforms is a newly identified biological mechanism, which has both implication in the development and aging of the CNS.

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In Vivo Chimeric Alzheimer’s Disease Modeling of Apolipoprotein E4 Toxicity in Human Neurons

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