. Cholesterol and matrisome pathways dysregulated in human APOE ε4 glia. bioRχiv, July 25, 2019

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  1. This is an exciting study demonstrating that APOE4 is associated with dysregulation of cholesterol homeostasis in human but not mouse astrocytes and microglia. Although such an association was implicated in previous studies, including those addressing APOE genotype effects in peripheral cells such as macrophages, this unbiased work demonstrates that in CNS-relevant glial cells, cholesterol metabolism likely represents a major APOE4-related pathobiology in Alzheimer’s and aging brains.

    It is also interesting that the defective cholesterol metabolism is unique to human cells. However, this observation should be interpreted with caution. In particular, it is known that primary cultured microglial cells behave very differently from when present in vivo. Other factors that could also impact the results, such as aging and sex, are difficult to be modeled and factored into consideration using cell culture systems.

    Future studies using, for example, single cell/single nucleus RNA sequencing in animal and human brains across different APOE genotype, age and sex with or without Alzheimer-related pathologies, might offer more definitive answers in terms of relevance to humans and in-vivo environments.

    View all comments by Guojun Bu
  2. This is an interesting and comprehensive whole-transcriptome study of APOE4 and Alzheimer’s disease (AD), using human iPSC-derived brain cells, mouse brain cells, and cell-type deconvoluted transcriptomic data from postmortem AD brains. An important finding is that APOE4 is associated with dysregulation of cholesterol homeostasis in human but not mouse astrocytes and microglia, suggesting a species-dependent effect of APOE4. In contrast, elevated matrisome signaling associated with chemotaxis, glial activation, and lipid biosynthesis is observed in APOE4 mixed human neuron/astrocyte culture, mouse APOE4 glial culture, and cell-type deconvoluted transcriptomic data of APOE4 glia from AD brains, suggesting that the effect of APOE4 on matrisome signaling is not species dependent.

    The human-specific transcriptional effect of APOE4 stresses the importance of studying APOE4 genotype-dependent effects in human model systems. In this regard, we have shown that APOE4 is associated with increased A production in human iPSC-derived neurons, but not in mouse neurons (Wang et al., 2018), again suggesting a species-dependent effect of APOE4. With increasing evidence of species differences in various aspects of AD modeling, it seems important to test drug candidates using human iPSC-derived brain cells before moving them into clinical trials in the future.

    One important question raised by this study is whether the human-specific effect of APOE4 on cholesterol homeostasis is a loss-of-function or a gain-of-detrimental-function in glial cells. It would be worth experimentally dissecting these opposite possibilities, since answering this question is crucial for potential therapeutic development based on this study.

    References:

    . Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat Med. 2018 May;24(5):647-657. Epub 2018 Apr 9 PubMed.

    View all comments by Yadong Huang
  3. This great and very extensive study by Julia TCW et al. demonstrates that the involvement of APOE4 in AD pathology likely falls back to the key role of ApoE in lipid metabolism. Additionally, they discovered a novel gene set/pathway called “matrisome” in APOE4 and AD cases. These findings are of tremendous importance to the field, since they make us researchers think about why APOE isoforms contribute to coronary artery disease, myocardial infarction, and AD in the same isoform-specific stepwise pattern: APOE4>APOE3>APOE2. Whereas this work demonstrates potential drawbacks of using animal models for complex human diseases, it suggests that hiPSC-derived brain cell cultures provide a translatable in vitro model to study APOE4-dysregulated pathways in AD.

    Please also check out the preLight article I wrote for this preprint: Cholesterol and matrisome pathways dysregulated in human APOE ε4 glia 

    I am excited to see it in the Sneak Peek with some additional data!

    View all comments by Theresa Pohlkamp

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  1. ApoE4 Glia Bungle Lipid Processing, Mess with the Matrisome