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Cited by 6Pluripotent Stem Cells ResearchAlzheimer's disease research and treatmentsNeurogenesis and neuroplasticity mechanisms

Generation of human induced pluripotent stem cell-derived cortical neurons expressing the six tau isoforms

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Jiang, Houbo, Xiao, Zichun, Saleem, Komal, Zhong, Ping, Li, Li, Chhetri, Gaurav, Li, Pei, Jiang, Zhongjiao +2 more·2025·Journal of Alzheimer’s Disease
DOI 10.1177/13872877251334831PMC PMC12754833
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Abstract

Background: The alternative splicing (AS) of MAPT , which encodes Tau, in the adult human brain produces six major isoforms that play critical roles in the pathogenesis of tauopathies including Alzheimer's disease. Previous efforts have failed to differentiate human induced pluripotent stem cells (hiPSCs) to cortical neurons expressing the six isoforms of Tau. Objective: We aim to develop a differentiation method capable of producing the six Tau isoforms in hiPSC-derived cortical neurons. Methods: We searched for the optimal concentration, duration and treatment window of morphogens in the differentiation of hiPSCs through embryoid bodies (EBs) to dorsal forebrain neuroepithelial cells then to cortical neurons. Results: The combined inhibition of WNT, SHH, and SMAD signaling in EBs generated neuroepithelial cells expressing appropriate dorsal forebrain markers, while suppressing ventral, midbrain, and hindbrain genes. Further differentiation in neurogenic and neurotrophic factors produced MAP2 + neurons at day 18. The iPSC-derived neurons expressed markers of all cortical layers and exhibited synapse formation and synaptic physiology. In addition, MAP2 + neurons and mitotic cells expressing radial glial markers formed aggregates that could be dissociated to produce mature neurons with similar properties. Most importantly, the six Tau isoforms were expressed from day 80 in a developmentally regulated manner, modeling the situation in human brains on an accelerated timeline. Conclusions: This chemically defined differentiation method produces a key hallmark of mature human cortical neurons by expressing the six main splicing isoforms of Tau. It will greatly facilitate disease modeling and therapeutic discovery for many human brain disorders involving cortical neurons.

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Cited by

Sorted by citations

Authors
Jiang, H., Xiao, Z., Saleem, K., Zhong, P., Li, L., Chhetri, G., Li, P., Jiang, Z., Yan, Z., & Feng, J.
Affiliations
University at Buffalo, State University of New York (US)
Corresponding author
Feng, Jian
ORCID
Venue
Journal of Alzheimer’s Disease
Publisher
SAGE Publications
Published
2025-04-23
Volume
105
Issue
4
Pages
1341-1354
ISSN
  • 1387-2877 (ISSN-L)
  • 1875-8908
DOI
10.1177/13872877251334831
PMC
PMC12754833
OpenAlex
W4409722724
Cited by
6
References
6
Citations by year
2026: 4 · 2025: 2
FWCI
1.80
Type
journal article
Language
en
Open access
Licence
journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations
  • Journal of Alzheimer s Disease (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
Funders
  • National Institute of Neurological Disorders and Stroke (NS113763, NS127728)
  • National Institute on Aging (AG079797, AG067597)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
human induced pluripotent stem cells, cortical neurons
MeSH terms
Cell Differentiation, Cells, Cultured, Cerebral Cortex, Humans, Neurons, tau Proteins, Protein Isoforms, Induced Pluripotent Stem Cells

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