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Lin YT, Seo J, Gao F, Feldman HM, Wen HL, Penney J, Cam HP, Gjoneska E, Raja WK, Cheng J, Rueda R, Kritskiy O, Abdurrob F, Peng Z, Milo B, Yu CJ, Elmsaouri S, Dey D, Ko T, Yankner BA, Tsai LH. APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types. Neuron. 2018 Jun 27;98(6):1141-1154.e7. Epub 2018 May 31 PubMed.
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Washington University
In Wang et al., the authors clearly demonstrate that there are several phenotypes seen in ApoE-4 versus ApoE3-expressing neurons derived from iPSC. They include increased tau phosphorylation, increased Aβ production, and a decrease in GABAergic neurons. The phenotypes appear clear because they can be reversed by gene editing. This is interesting as it suggests that, despite low levels of ApoE expression by neurons, ApoE4 can somehow still result in a neuronal phenotype, at least under these culture conditions. This provides a new model system to test agents that can reverse these phenotypes as well as study mechanism. What is not clear is which phenotypes are relevant in the in vivo setting when there are many other cell types present, including glia, which produce much more ApoE than neurons.
In Lin et al., the authors assess iPSC-induced neurons, astrocytes, and microglia derived from ApoE3/E3 and ApoE4/E4 individuals. Interestingly, all the cell types have gene-expression phenotypes indicating that ApoE can have effects in all cells in a cell-autonomous fashion. The gene changes are most extensive between genotypes in microglia. This is consistent with several recent results suggesting effects of ApoE on microglia, under certain conditions, can affect the innate immune response and drive neurodegeneration. As with the Lin et al. paper, what is not clear is which phenotypes are relevant in the in vivo setting when there are many other cell types present together. However, this does provide a new model system as well to ask specific questions about ApoE biology.
View all comments by David HoltzmanUniversity of South Florida
The recent emphasis on Alzheimer’s disease drug development has produced therapeutics with promising results for various stages of pathology in AD mouse models, but unfortunately these strategies fail in human clinical trials. Using human iPSCs (hiPSC) from homozygous ApoE3 and ApoE4 individuals, Huang and colleagues were able to compare AD-related pathology between these two genetic cell lines and in gene-edited isogenic and ApoE-deficient hiPSC lines. Human ApoE4-expressing cells showed many results confirming previous mouse model data in regard to increased tau phosphorylation, greater soluble APP detected, and enhanced Aβ production.
With these cell lines, the question of whether ApoE4 represents a loss of normal ApoE function or a gain of toxic function could be proposed. Reintroduction of ApoE4 into ApoE-deficient hiPSCs recapitulated the ApoE4 hiPSC phenotype, suggesting the latter of the two possibilities. These results were supported by the group’s introduction of a small molecule “structural corrector” that can change the ApoE4 structure in that of ApoE3. Its use ameliorates the pathology established in the ApoE4 hiPSCs, indicating that the secession of the toxic effects from ApoE4 can rescue the major established pathological phenotypes.
What could the mechanism of toxic action be that is specific to ApoE4? Lin et al. may provide insight. Similar hiPSCs from homozygous individuals are used in this study, as well, and also reveal amelioration of pathology in both neurons and glia when a CRISPR/Cas9 approach is used to convert ApoE4 expression to that of ApoE3. Lin et al. observed a reduction of both ApoE4 protein and mRNA in their ApoE4-astrocyte cell line, suggesting a negative transcriptional regulation of ApoE4 on itself. Further transcriptional analysis of ApoE4-expressing neurons, glia, and astrocytes showed significant changes in numerous genes, in particular those genes associated with lipid metabolism and protein transport.
Clearance of Aβ has historically been the focus of ApoE isoform function, but recent reports have minimized the potential for significant in vivo interactions of ApoE and amyloid. Regardless, ApoE4 remains as the greatest genetic contributor for sporadic AD risk. These studies nicely demonstrate the usefulness of hiPSCs and provide insight into the possible consequences of altered gene expression dependent on presence of ApoE4.
Questions of ApoE2 actions on gene expression, peripheral gene targets for AD intervention and small molecule therapeutic design in light of these results have yet to be addressed. Moreover, time will tell if the utility of human cell lines to better understand fundamental AD pathogenic processes will translate into desperately needed success in human clinical trials.
View all comments by Edwin J. WeeberUniversity of New South Wales
These are two interesting studies shedding new light on APOE4 and its role on Aβ production/clearance by different CNS cell types and neuronal tau pathology.
I was particularly intrigued by the finding in Shi et al. that not reduction of Aβ but the small molecule-mediated change to APOE4 reduced tau phosphorylation in the cells. This provides further evidence for an intimate connection between APOE4 and tau in Alzheimer’s disease, as recently nicely shown by the Holtzman lab (Shi et al., 2017).
We certainly need to see next if a small-molecule corrector of APOE4 will improve deficits in relevant in vivo models of Alzheimer’s disease.
Eds: This comment has been edited to correct the citation.
References:
Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, Tsai RM, Spina S, Grinberg LT, Rojas JC, Gallardo G, Wang K, Roh J, Robinson G, Finn MB, Jiang H, Sullivan PM, Baufeld C, Wood MW, Sutphen C, McCue L, Xiong C, Del-Aguila JL, Morris JC, Cruchaga C, Alzheimer’s Disease Neuroimaging Initiative, Fagan AM, Miller BL, Boxer AL, Seeley WW, Butovsky O, Barres BA, Paul SM, Holtzman DM. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017 Sep 28;549(7673):523-527. Epub 2017 Sep 20 PubMed.
View all comments by Lars M. IttnerThese two complementary papers provide new insight on the mechanisms by which APOE4 could drive Alzheimer’s disease. Both studies used CRISPR/Cas9 and iPSCs to examine APOE4 effects on human brain cell types. In Lin et al., a striking observation is that APOE4 microglia-like cells exhibit impaired Aβ peptide uptake and a clear inflammatory transcriptomic profile. Such new insights were only made possible with the advent of new protocols to differentiate macrophages from iPSCs.
Beyond these exciting APOE4 variant-driven mechanistic insights, and especially the realization that each brain cell type behaves differently, these two studies used an experimental approach that can be extended to other molecules/variants involved in AD as well as other neurological diseases.
With the combined resolution of bulk transcriptomic analysis, as well as the advent of CRISPR-CAS9 gene editing and the development of advanced tissue organoids, it will become possible to understand the specific molecular factors involved in the pathophysiology of disease and how their dysregulation can lead to pathologies in humans as well as lead to novel therapeutic targets. These are exciting prospects for the future.
View all comments by Florent GinhouxHarvard Medical School and Brigham&Women's Hospital
See also Jessica Young's recent paper, which also shows tau effects in AD patient-derived neurons independent of APP (Young et al., 2018).
As for a small molecule corrector of ApoE4 deficits, yes, that is one approach, but I would argue that a more profitable line of attack based on human genetics is likely to be trying ApoE2 gene therapy.
References:
Young JE, Fong LK, Frankowski H, Petsko GA, Small SA, Goldstein LS. Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein. Stem Cell Reports. 2018 Mar 13;10(3):1046-1058. Epub 2018 Mar 1 PubMed.
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