Limitations of the human iPSC-derived neuron model for early-onset Alzheimer's disease

Phoebe Valdes; Kenneth W Henry; Michael Q Fitzgerald; Koushik Muralidharan; Andrew B Caldwell; Srinivasan Ramachandran; Lawrence S B Goldstein; William C Mobley; Douglas R Galasko; Shankar Subramaniam

doi:10.1186/s13041-023-01063-5

Limitations of the human iPSC-derived neuron model for early-onset Alzheimer's disease

Mol Brain. 2023 Nov 3;16(1):75. doi: 10.1186/s13041-023-01063-5.

Authors

Phoebe Valdes^{1

2}, Kenneth W Henry^{3

4}, Michael Q Fitzgerald^{1

2}, Koushik Muralidharan^{5

6}, Andrew B Caldwell¹, Srinivasan Ramachandran¹, Lawrence S B Goldstein^{3

7}, William C Mobley⁸, Douglas R Galasko⁸, Shankar Subramaniam^{9

10

11

12}

Affiliations

¹ Department of Bioengineering, University of California, La Jolla, San Diego, CA, USA.
² Bioengineering Graduate Program, University of California, La Jolla, San Diego, CA, USA.
³ Department of Cellular and Molecular Medicine, University of California, La Jolla, San Diego, CA, USA.
⁴ Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
⁵ Medical Scientist Training Program, University of California, La Jolla, San Diego, CA, USA.
⁶ School of Medicine, University of California, La Jolla, San Diego, CA, USA.
⁷ Sanford Stem Cell Clinical Center, University of California, La Jolla, San Diego, CA, USA.
⁸ Department of Neurosciences, University of California, La Jolla, San Diego, CA, USA.
⁹ Department of Bioengineering, University of California, La Jolla, San Diego, CA, USA. shankar@ucsd.edu.
¹⁰ Department of Cellular and Molecular Medicine, University of California, La Jolla, San Diego, CA, USA. shankar@ucsd.edu.
¹¹ Department of Nanoengineering, University of California, La Jolla, San Diego, CA, USA. shankar@ucsd.edu.
¹² Department of Computer Science and Engineering, University of California, La Jolla, San Diego, CA, USA. shankar@ucsd.edu.

Abstract

Non-familial Alzheimer's disease (AD) occurring before 65 years of age is commonly referred to as early-onset Alzheimer's disease (EOAD) and constitutes ~ 5-6% of all AD cases (Mendez et al. in Continuum 25:34-51, 2019). While EOAD exhibits the same clinicopathological changes such as amyloid plaques, neurofibrillary tangles (NFTs), brain atrophy, and cognitive decline (Sirkis et al. in Mol Psychiatry 27:2674-88, 2022; Caldwell et al. in Mol Brain 15:83, 2022) as observed in the more prevalent late-onset AD (LOAD), EOAD patients tend to have more severe cognitive deficits, including visuospatial, language, and executive dysfunction (Sirkis et al. in Mol Psychiatry 27:2674-88, 2022). Patient-derived induced pluripotent stem cells (iPSCs) have been used to model and study penetrative, familial AD (FAD) mutations in APP, PSEN1, and PSEN2 (Valdes et al. in Research Square 1-30, 2022; Caldwell et al. in Sci Adv 6:1-16, 2020) but have been seldom used for sporadic forms of AD that display more heterogeneous disease mechanisms. In this study, we sought to characterize iPSC-derived neurons from EOAD patients via RNA sequencing. A modest difference in expression profiles between EOAD patients and non-demented control (NDC) subjects resulted in a limited number of differentially expressed genes (DEGs). Based on this analysis, we provide evidence that iPSC-derived neuron model systems, likely due to the loss of EOAD-associated epigenetic signatures arising from iPSC reprogramming, may not be ideal models for studying sporadic AD.

Keywords: Early-onset Alzheimer’s disease; RNA-seq; Systems biology; iPSC neurons.

MeSH terms

Alzheimer Disease* / genetics
Alzheimer Disease* / pathology
Humans
Induced Pluripotent Stem Cells* / pathology
Mutation / genetics
Neurons / pathology

Abstract

MeSH terms

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