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

Autor: Valdes P; Department of Bioengineering, University of California, La Jolla, San Diego, CA, USA.; Bioengineering Graduate Program, University of California, La Jolla, San Diego, CA, USA., Henry KW; Department of Cellular and Molecular Medicine, University of California, La Jolla, San Diego, CA, USA.; Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA., Fitzgerald MQ; Department of Bioengineering, University of California, La Jolla, San Diego, CA, USA.; Bioengineering Graduate Program, University of California, La Jolla, San Diego, CA, USA., Muralidharan K; Medical Scientist Training Program, University of California, La Jolla, San Diego, CA, USA.; School of Medicine, University of California, La Jolla, San Diego, CA, USA., Caldwell AB; Department of Bioengineering, University of California, La Jolla, San Diego, CA, USA., Ramachandran S; Department of Bioengineering, University of California, La Jolla, San Diego, CA, USA., Goldstein LSB; Department of Cellular and Molecular Medicine, University of California, La Jolla, San Diego, CA, USA.; Sanford Stem Cell Clinical Center, University of California, La Jolla, San Diego, CA, USA., Mobley WC; Department of Neurosciences, University of California, La Jolla, San Diego, CA, USA., Galasko DR; Department of Neurosciences, University of California, La Jolla, San Diego, CA, USA., Subramaniam S; Department of Bioengineering, University of California, La Jolla, San Diego, CA, USA. shankar@ucsd.edu.; Department of Cellular and Molecular Medicine, University of California, La Jolla, San Diego, CA, USA. shankar@ucsd.edu.; Department of Nanoengineering, University of California, La Jolla, San Diego, CA, USA. shankar@ucsd.edu.; Department of Computer Science and Engineering, University of California, La Jolla, San Diego, CA, USA. shankar@ucsd.edu.
Jazyk: angličtina
Zdroj: Molecular brain [Mol Brain] 2023 Nov 03; Vol. 16 (1), pp. 75. Date of Electronic Publication: 2023 Nov 03.
DOI: 10.1186/s13041-023-01063-5
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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