Limitations of the human iPSC-derived neuron model for early-onset Alzheimer's disease - PubMed (original) (raw)

Limitations of the human iPSC-derived neuron model for early-onset Alzheimer's disease

Phoebe Valdes et al. Mol Brain. 2023.

Abstract

Non-familial Alzheimer's disease (AD) occurring before 65 years of age is commonly referred to as early-onset Alzheimer's disease (EOAD) and constitutes ~ 5-6% of all AD cases (Mendez et al. in Continuum 25:34-51, 2019). While EOAD exhibits the same clinicopathological changes such as amyloid plaques, neurofibrillary tangles (NFTs), brain atrophy, and cognitive decline (Sirkis et al. in Mol Psychiatry 27:2674-88, 2022; Caldwell et al. in Mol Brain 15:83, 2022) as observed in the more prevalent late-onset AD (LOAD), EOAD patients tend to have more severe cognitive deficits, including visuospatial, language, and executive dysfunction (Sirkis et al. in Mol Psychiatry 27:2674-88, 2022). Patient-derived induced pluripotent stem cells (iPSCs) have been used to model and study penetrative, familial AD (FAD) mutations in APP, PSEN1, and PSEN2 (Valdes et al. in Research Square 1-30, 2022; Caldwell et al. in Sci Adv 6:1-16, 2020) but have been seldom used for sporadic forms of AD that display more heterogeneous disease mechanisms. In this study, we sought to characterize iPSC-derived neurons from EOAD patients via RNA sequencing. A modest difference in expression profiles between EOAD patients and non-demented control (NDC) subjects resulted in a limited number of differentially expressed genes (DEGs). Based on this analysis, we provide evidence that iPSC-derived neuron model systems, likely due to the loss of EOAD-associated epigenetic signatures arising from iPSC reprogramming, may not be ideal models for studying sporadic AD.

Keywords: Early-onset Alzheimer’s disease; RNA-seq; Systems biology; iPSC neurons.

© 2023. The Author(s).

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1

Fig. 1

A Non-demented controls (NDCs) and EOAD iPSCs were differentiated using dual SMAD inhibitors (first step) and basic-FGF withdrawal (second step). B Metadata for NDC and EOAD subjects used in this study. C Multi-dimensional scaling (MDS) analysis after batch correction by experimental condition, sex and sequencing batch of filtered normalized RNA-seq data. D RNA-seq volcano plot of differentially expressed genes (DEGs) for EOAD patients relative to all NDCs as determined by kimma with an FDR p-value < 0.05. E Quasi-proportional Venn diagram overlap of DEGs across the four EOAD patients relative to all NDC subject neurons. F MDS (left) and UMAP (right) analysis based on NDC and EOAD neurons generated in this study using filtered, normalized RNA-seq data. G RNA expression profile heatmap corresponding to all filtered genes. H MDS (left) and UMAP (right) analysis based on NDC and EOAD neurons generated in this study using filtered, normalized RNA-seq data for neuron lineage genes. I RNA expression profile heatmap corresponding to either neuron lineage genes (left) or post-mitotic genes (right) clustered by subject experimental condition (NDC or EOAD)

References

    1. Mendez MF. Early-onset Alzheimer Disease and Its Variants. Continuum (Minneap Minn). 2019;25:34–51. -PMC -PubMed
    1. Sirkis DW, Bonham LW, Johnson TP, La Joie R, Yokoyama JS. Dissecting the clinical heterogeneity of early-onset Alzheimer’s disease. Mol Psychiatry. 2022;27:2674–2688. doi: 10.1038/s41380-022-01531-9. -DOI -PMC -PubMed
    1. Caldwell AB, Anantharaman BG, Ramachandran S, Nguyen P, Liu Q, Trinh I, et al. Transcriptomic profiling of sporadic Alzheimer’s disease patients. Mol Brain. 2022;15:83. doi: 10.1186/s13041-022-00963-2. -DOI -PMC -PubMed
    1. Valdes P, Caldwell A, Liu Q, Fitzgerald M, Ramachandran S, Karch C, et al. Integrative multiomics reveals common endotypes across PSEN1, PSEN2, and APP mutations in familial Alzheimer’s disease. Research Square. 2022;1-30. 10.21203/rs.3.rs-2356131/v1
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