Lagomarsino VN, Pearse RV 2nd, Liu L, Hsieh YC, Fernandez MA, Vinton EA, Paull D, Felsky D, Tasaki S, Gaiteri C, Vardarajan B, Lee H, Muratore CR, Benoit CR, Chou V, Fancher SB, He A, Merchant JP, Duong DM, Martinez H, Zhou M, Bah F, Vicent MA, Stricker JM, Xu J, Dammer EB, Levey AI, Chibnik LB, Menon V, Seyfried NT, De Jager PL, Noggle S, Selkoe DJ, Bennett DA, Young-Pearse TL. Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors. Neuron. 2021 Nov 3;109(21):3402-3420.e9. Epub 2021 Sep 1 PubMed.

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  1. This is a creative application of iPSC technologies, but also showcases some of the challenges in cellular modeling of sporadic neurodegenerative diseases. The authors performed an innovative cross-analysis of data from iPSC-derived neurons and matched postmortem brain from healthy and AD individuals, identifying potential dysregulated pathways in AD. Rich clinical phenotyping was performed on all of the iPSC donors as part of the ROS and MAP cohorts, adding further value to the published datasets.

    However, as the authors note, the effect sizes observed in the iPSC neuron experiments were quite small, despite the use of robust NGN2-based differentiation methods. This is potentially due to multiple factors, including inherent variability across iPSC lines and genetic differences among donors, coupled with the (likely) divergent biology of sporadic AD and relatively modest sample sizes (n=16 LOAD).

    It will be interesting to see whether iPSC-based studies of other sporadic neurodegenerative diseases—such as those being undertaken by Answer ALS—are able to overcome these challenges by employing substantially higher sample sizes of greater than 1,000 participants. In the future, it will also be interesting to directly compare lines that harbor familial mutations and lines from individuals with sporadic disease.

    View all comments by Michael Ward

  2. Reading this paper in Neuron felt extremely real on many levels. I am thankful to the authors for providing such an outstandingly useful resource to the field. It will accelerate discovery in the Alzheimer's field.

    This was a humongous tour de force, not only for the deep multi-omic and functional phenotyping work, but also for the clear, logical, honest data analysis that takes into account a realistic representation of individual variability in pathology, cognition, and iPSC neuronal phenotypes.

    I was pleasantly surprised to see that the authors were able to find a significant association between amyloid and tau in iPSC neurons and the cognitive trajectories in the same individuals. These data suggest that, at least for a subset of "high pathology" patients, established disease pathways are linked to genetic risk, and can be used as in vitro readouts also for sporadic LOAD models. I was not necessarily expecting this. 

    Among the many experimental possibilities this opens, I am particularly excited that iPSC derivatives from this resource can be used to probe for the influence of diverse aging factors, which, when added to this rejuvenated system, may intensify known AD-associated phenotypes, and initiate other AD-pathogenic events.

    View all comments by Jerome Mertens

  3. Really nice study. Similarly, we found in a cohort of about 35 sporadic ALS iPS cell lines and C9ORF72 iPS neuronal lines, derived from PBMC and not fibroblasts, that the protein and pathophysiological events very closely mirrored that found in autopsy cortex from sporadic and C9ORF72 ALS patients (Coyne et al., 2020; Coyne et al., 2021).

    There is no question that iPS cells can serve as a foundational tool to unravel cell biological events in these diseases. However, one needs to look at larger number of iPS lines, no different than examining multiple patients. Studies in a few iPS lines, especially for sporadic disorders, require large number of lines—not a handful—to be scientifically meaningful.

    Although some argue the need to use fibroblasts as a starting point, clearly, emerging and robust data suggest that blood-derived iPS lines can very closely mirror the actual cell biological defect found in authentic human autopsy materials.

    References:

    Coyne AN, Zaepfel BL, Hayes L, Fitchman B, Salzberg Y, Luo EC, Bowen K, Trost H, Aigner S, Rigo F, Yeo GW, Harel A, Svendsen CN, Sareen D, Rothstein JD. G4C2 Repeat RNA Initiates a POM121-Mediated Reduction in Specific Nucleoporins in C9orf72 ALS/FTD. Neuron. 2020 Sep 23;107(6):1124-1140.e11. Epub 2020 Jul 15 PubMed.

    Coyne AN, Baskerville V, Zaepfel BL, Dickson DW, Rigo F, Bennett F, Lusk CP, Rothstein JD. Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS. Sci Transl Med. 2021 Jul 28;13(604) PubMed.

    View all comments by Jeffrey D. Rothstein

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  1. iPSC-Derived Neurons Mirror LOAD Pathologies of Their Donors