Mertens J, Herdy JR, Traxler L, Schafer ST, Schlachetzki JC, Böhnke L, Reid DA, Lee H, Zangwill D, Fernandes DP, Agarwal RK, Lucciola R, Zhou-Yang L, Karbacher L, Edenhofer F, Stern S, Horvath S, Paquola AC, Glass CK, Yuan SH, Ku M, Szücs A, Goldstein LS, Galasko D, Gage FH. Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer's patients. Cell Stem Cell. 2021 Sep 2;28(9):1533-1548.e6. Epub 2021 Apr 27 PubMed.

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  1. The paper by Mertens et al. identifies an important approach to using human cells in the context of both sporadic and familial AD. One especially intriguing possibility would be to identify specific age-related pathways that the fibroblast-derived neurons possess and use those pathways to age iPSCs. As demonstrated by Mertens et al., iPSC-derived neurons more closely resemble fetal neurons than adult neurons, so an ability to identify specific aging pathways that interact with genetic mutations would be a big step forward for the field. It should be noted that there are other aging mimics that have been used to try to address this problem (Miller et al., 2013; Vera et al., 2016), although there are some caveats about how well they may work (Pandya et al., 2021). 

    It is also important to note that other groups have indeed seen significant transcriptional abnormalities in iPSC-derived neurons harboring familial ADRD mutations in well-controlled studies (Kwart et al., 2019, and Guttikonda et al., 2021, were  covered by Alzforum previously). There appear to be overlapping transcriptional signatures between these different studies, which likely implies that there are similarities between inherited and sporadic AD cases. Furthermore, for highly penetrant variants, we may be able to readily identify molecular signatures related to disease process, even in relatively immature cells. The choice of platform will likely be informed by whether one wishes to examine single monogenic causes of disease or try to capture more subtle polygenic risk, for which the relative effect of aging may be more substantial.

    While the direct reprogramming of aged fibroblast into derived neurons is both technically and conceptually important, there are currently some limitations. They include 1) lack of an ability to efficiently genome-engineer fibroblasts, making generation of isogenic controls difficult, and 2) challenges in scaling up experiments due to slow growth and limited outgrowth potential. This results in significant hurdles to disseminating cell reagents to the community and prohibits certain types of experiments that require large cell numbers. For these reasons, our strategy in the IPSC Neurodegenerative Disease Initiative complements experiments performed in fibroblast-derived neurons (Ramos et al., 2021). 

    An isogenic series of mutant lines may be an appropriate strategy for creating cell models of relatively highly penetrant ADRD alleles that can be disseminated to other researchers and will likely enable us to identify molecular convergences across gene mutations that would otherwise be masked by intergenic variability across lines from different patients. Per George Edward Pelham Box’s aphorism, all models are wrong, but it remains our aspiration that some models might be useful.

    References:

    Miller JD, Ganat YM, Kishinevsky S, Bowman RL, Liu B, Tu EY, Mandal PK, Vera E, Shim JW, Kriks S, Taldone T, Fusaki N, Tomishima MJ, Krainc D, Milner TA, Rossi DJ, Studer L. Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell. 2013 Dec 5;13(6):691-705. PubMed.

    Vera E, Bosco N, Studer L. Generating Late-Onset Human iPSC-Based Disease Models by Inducing Neuronal Age-Related Phenotypes through Telomerase Manipulation. Cell Rep. 2016 Oct 18;17(4):1184-1192. PubMed.

    Pandya VA, Crerar H, Mitchell JS, Patani R. A Non-Toxic Concentration of Telomerase Inhibitor BIBR1532 Fails to Reduce TERT Expression in a Feeder-Free Induced Pluripotent Stem Cell Model of Human Motor Neurogenesis. Int J Mol Sci. 2021 Mar 23;22(6) PubMed.

    Kwart D, Gregg A, Scheckel C, Murphy EA, Paquet D, Duffield M, Fak J, Olsen O, Darnell RB, Tessier-Lavigne M. A Large Panel of Isogenic APP and PSEN1 Mutant Human iPSC Neurons Reveals Shared Endosomal Abnormalities Mediated by APP β-CTFs, Not Aβ. Neuron. 2019 Oct 23;104(2):256-270.e5. Epub 2019 Aug 12 PubMed.

    Guttikonda SR, Sikkema L, Tchieu J, Saurat N, Walsh RM, Harschnitz O, Ciceri G, Sneeboer M, Mazutis L, Setty M, Zumbo P, Betel D, de Witte LD, Pe'er D, Studer L. Fully defined human pluripotent stem cell-derived microglia and tri-culture system model C3 production in Alzheimer's disease. Nat Neurosci. 2021 Mar;24(3):343-354. Epub 2021 Feb 8 PubMed.

    Ramos DM, Skarnes WC, Singleton AB, Cookson MR, Ward ME. Tackling neurodegenerative diseases with genomic engineering: A new stem cell initiative from the NIH. Neuron. 2021 Apr 7;109(7):1080-1083. PubMed.

    View all comments by Andrew Singleton

  2. In this groundbreaking work, Mertens and colleagues compare the transcription profiles in AD and control neurons derived either directly from fibroblasts or from iPSC cells from the same donors. The directly induced neurons maintain epigenetic changes associated with aging, while the iPSC cells are reprogrammed and lose this signature. The differences in gene expression between control fibroblast- and AD fibroblast-derived neurons are striking and indicate an important role for age-related “epigenetic erosion” in the development of AD. This is corroborated by demonstrating that the AD expression profile is lost when iPSC cells are used to generate neurons.

    The work provides a great model to study the link between aging and neurodegeneration. It turns reasoning in the field upside down, suggesting that the pathological phenotype in AD is a consequence of pathological aging manifested as epigenetic alteration. The question is whether anything specific (e.g., polygenic risk) is upstream to this pathological profile.

    One wonders what the secret is to maintaining a healthy epigenetic profile in the brain in very old age, as seen in the centenarian cohorts of Henne Holstege. More down to earth is how the defining neuropathological signature of AD relates to the pathological transcriptional signatures identified here. The fact that the latter are captured in neurons derived from fibroblasts that were not exposed to amyloid or tangle pathology suggests cell-autonomous, upstream effects. How these then affect mechanisms that result in the classical neuropathology remains to be seen.

    A further development of the approach would be to integrate these neurons into more complex multicellular models of disease to learn how the epigenetic erosion in neurons (or other cells) affects vascular-glia-neuron interactions.

    View all comments by Bart De Strooper

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  1. Neurons Made from Fibroblasts Keep Imprint of Alzheimer's, Aging