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Dedifferentiation and neuronal repression define familial Alzheimer's disease

Andrew B Caldwell1, Qing Liu2, Gary P Schroth3

  • 1Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.

Science Advances
|November 14, 2020
PubMed

Insights

Changes in chromatin topology trigger Alzheimer's disease mechanisms like neuronal dedifferentiation. These findings in patient-derived neurons and brains offer new therapeutic targets for Alzheimer's disease (AD).

Area of Science:

  • Neuroscience
  • Genetics
  • Stem Cell Biology

Background:

  • Alzheimer's disease (AD) pathogenesis involves complex systems-level mechanisms, representing a significant unmet therapeutic need.
  • Understanding these mechanisms is crucial for developing effective treatments.

Purpose of the Study:

  • To identify the systems-level mechanisms driving Alzheimer's disease.
  • To investigate the role of chromatin topology in neuronal dedifferentiation and identity repression in early-onset familial Alzheimer's disease (EOFAD).

Main Methods:

  • Generation of human induced pluripotent stem cell (hiPSC)-derived neurons from EOFAD patients.
  • Multiomics approach including RNA-seq, ATAC-seq, and ChIP-seq.
  • Validation of findings in EOFAD patient brains.

Main Results:

  • EOFAD neurons exhibit dedifferentiation into a precursor-like state with ectoderm and nonectoderm lineage signatures.
  • Transcriptional alterations are driven by changes in histone methylation and chromatin topology.
  • Identified mechanisms are conserved in EOFAD patient brains, validating the hiPSC model.

Conclusions:

  • Chromatin topology alterations are key drivers of Alzheimer's disease-causative mechanisms.
  • Dedifferentiation and loss of neuronal identity are linked to epigenetic and topological changes.
  • Uncovered mechanistic endotypes provide critical insights for novel therapeutic interventions in Alzheimer's disease.

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