Human iPSC-Derived Hippocampal Spheroids: An Innovative Tool for Stratifying Alzheimer Disease Patient-Specific Cellular Phenotypes and Developing Therapies

Stem Cell Reports. 2020 Jul 14;15(1):256-273. doi: 10.1016/j.stemcr.2020.06.001. Epub 2020 Jun 25.

Abstract

The hippocampus is important for memory formation and is severely affected in the brain with Alzheimer disease (AD). Our understanding of early pathogenic processes occurring in hippocampi in AD is limited due to tissue unavailability. Here, we report a chemical approach to rapidly generate free-floating hippocampal spheroids (HSs), from human induced pluripotent stem cells. When used to model AD, both APP and atypical PS1 variant HSs displayed increased Aβ42/Aβ40 peptide ratios and decreased synaptic protein levels, which are common features of AD. However, the two variants differed in tau hyperphosphorylation, protein aggregation, and protein network alterations. NeuroD1-mediated gene therapy in HSs-derived progenitors resulted in modulation of expression of numerous genes, including those involved in synaptic transmission. Thus, HSs can be harnessed to unravel the mechanisms underlying early pathogenic changes in the hippocampi of AD patients, and provide a robust platform for the development of therapeutic strategies targeting early stage AD.

Keywords: Alzheimer disease; NeuroD1; hippocampus; iPSC; protein aggregation; proteomics; spheroids; transcriptomics; viral-mediated gene therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Case-Control Studies
  • Genetic Therapy
  • Hippocampus / pathology*
  • Humans
  • Induced Pluripotent Stem Cells / pathology*
  • Neurons / pathology
  • Phenotype
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism
  • Protein Aggregates
  • Proteome / metabolism
  • Proteomics
  • Spheroids, Cellular / pathology*
  • Transcription, Genetic

Substances

  • Amyloid beta-Protein Precursor
  • Presenilin-1
  • Protein Aggregates
  • Proteome