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Human-Induced Neurons from Presenilin 1 Mutant Patients Model Aspects of Alzheimer’s Disease Pathology

Schrank, Sean, McDaid, John, Briggs, Clark A., Mustaly-Kalimi, Sarah, Brinks, Deanna, Houcek, Aiden, Singer, Oded, Bottero, Virginie, Marr, Robert A., Stutzmann, Grace E.·2020·International Journal of Molecular Sciences
DOI 10.3390/ijms21031030PMC PMC7037274
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Abstract

Traditional approaches to studying Alzheimer’s disease (AD) using mouse models and cell lines have advanced our understanding of AD pathogenesis. However, with the growing divide between model systems and clinical therapeutic outcomes, the limitations of these approaches are increasingly apparent. Thus, to generate more clinically relevant systems that capture pathological cascades within human neurons, we generated human-induced neurons (HiNs) from AD and non-AD individuals to model cell autonomous disease properties. We selected an AD patient population expressing mutations in presenilin 1 (mPS1), which is linked to increased amyloid production, tau pathology, and calcium signaling abnormalities, among other features. While these AD components are detailed in model systems, they have yet to be collectively identified in human neurons. Thus, we conducted molecular, immune-based, electrophysiological, and calcium imaging studies to establish patterns of cellular pathology in this patient population. We found that mPS1 HiNs generate increased Aβ42 and hyperphosphorylated tau species relative to non-AD controls, and exaggerated ER calcium responses that are normalized with ryanodine receptor (RyR) negative allosteric modulators. The inflammasome product, interleukin-18 (IL-18), also increased PS1 expression. This work highlights the potential for HiNs to model AD pathology and validates their role in defining cellular pathogenesis and their utility for therapeutic screening.

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  • Studies using human iPSC-derived neurons demonstrate that the PSEN1 M146L mutation significantly elevates the Aβ42/Aβ40 ratio by selectively increasing Aβ42 production without altering Aβ40 levels, a biochemical signature strongly linked to amyloid aggregation and neurotoxicity in AD.

    “Moreover, studies utilizing human induced pluripotent stem cell (iPSC)-derived neurons demonstrate that the M146L mutation significantly elevates the Aβ42/Aβ40 ratio by selectively increasing Aβ42 production without altering Aβ40 levels, a biochemical signature strongly linked to amyloid aggregation and neurotoxicity in AD (Liu et al. 2014), (Sproul et al. 2014), (Schrank et al. 2020).”

    From TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models (2026) · cites this paper as Schrank et al. 2020

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Metadata

Authors
Schrank, S., McDaid, J., Briggs, C. A., Mustaly-Kalimi, S., Brinks, D., Houcek, A., Singer, O., Bottero, V., Marr, R. A., & Stutzmann, G. E.
Affiliations
  • Center for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
  • Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Rd. North, Chicago, IL 60064, USA
  • Lake Forest College, Lake Forest, IL 60045, USA
  • Weizmann Institute of Science, Life Sciences Core Facilities, Rehovot 76100, Israel
ORCID
Stutzmann, Grace E.
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2020-02-04
Volume
21
Issue
3
Pages
1030
ISSN
1422-0067
DOI
10.3390/ijms21031030
PMC
PMC7037274
Cited by
22
References
6
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
National Institutes of Health (1 R01 AG047237, 1 R21 AG048615)

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