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Publications

Journal Article Ppublish

PubMed: 42635110 DOI: 10.1002/alz.71776

Disruption of hippocampal upstream regulators of mTOR and insulin pathways in Down syndrome with Alzheimer's disease neuropathology: Preliminary observations.

Alzheimers Dement 22(8):e71776

Authors: Abigail J Nordbeck, Mitchell Martá-Ariza, Henric Ek Olofsson, Evgeny Kanshin, Beatrix Ueberheide, Ken Jones, Bridget Sanford, Eric D Hamlett, Elizabeth Head, Elliott J Mufson, Sylvia E Perez, Thomas Wisniewski, Samuel Guzman, Ann-Charlotte Granholm

Affiliations

  • Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
  • Center for Cognitive Neurology, Department of Neurology, New York University Grossman School of Medicine, New York, New York, USA.
  • Proteomics Laboratory, Division of Advanced Research Technologies, New York University Grossman School of Medicine, New York, New York, USA.
  • Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, New York, USA.
  • Department of Neurology, New York University Grossman School of Medicine, New York, New York, USA.
  • Department of Cell and Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. Bioinformatic Solutions LLC, Sheridan, Wyoming, USA.
  • Bioinformatic Solutions LLC, Sheridan, Wyoming, USA.
  • Department of Pathology & Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
  • Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, California, USA.
  • Department of Translational Neuroscience and Neurology, Barrow Neurological Institute, Phoenix, Arizona, USA.
  • Departments of Pathology and Psychiatry, New York University Grossman School of Medicine, New York, New York, USA.
  • Department of Pathology and Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

Abstract

INTRODUCTION

Down syndrome (DS) is caused by a complete or partial trisomy of chromosome 21, resulting in variable intellectual disabilities and a high risk for early-onset Alzheimer's disease (DS-AD). Dysregulation of the mammalian target of rapamycin (mTOR) and insulin (INS) signaling pathways has been reported in DS. We hypothesized that upstream alterations in these two pathways contribute to hippocampal dysfunction in DS-AD.

METHODS

We used spatial transcriptomics and localized proteomic techniques to examine mTOR/INS signaling pathways in subregions of the hippocampus in post mortem tissue from individuals with DS-AD and age-matched neurotypical controls.

RESULTS

mTOR pathways were significantly altered in specific hippocampal subfields in DS-AD, and INS pathways were significantly altered in dentate granule neurons.

DISCUSSION

These preliminary spatial transcriptomics and localized proteomics findings demonstrate an interplay between select hippocampal mTOR/INS pathways and cellular populations, suggesting potential novel drug targets and early biomarkers for DS.

MeSH

Dementia, Down Syndrome, Insulin, Alzheimer Disease, Neuropathology, Tor Serine-Threonine Kinases, Spatial Transcriptomics