Skip to main content

ORIGINAL RESEARCH article

Front. Mol. Neurosci.
Sec. Neuroplasticity and Development
Volume 18 - 2025 | doi: 10.3389/fnmol.2025.1546375
This article is part of the Research Topic Molecular neuroscience of cognitive resilience View all articles

Profiling hippocampal neuronal populations reveals unique gene expression mosaics reflective of connectivity-based degeneration in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease

Provisionally accepted
Melissa Alldred Melissa Alldred 1Kyrillos W. Ibrahim Kyrillos W. Ibrahim 1Harshitha Pidikiti Harshitha Pidikiti 1Sanghan Lee Sanghan Lee 1Adriana Heguy Adriana Heguy 2Gabriela Chiosis Gabriela Chiosis 3Elliott Jay Mufson Elliott Jay Mufson 4Beth Stutzmann Beth Stutzmann 5Stephen D Ginsberg Stephen D Ginsberg 1*
  • 1 Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, United States
  • 2 Grossman School of Medicine, New York University, New York, New York, United States
  • 3 Chemical Biology Program, Sloan Kettering Insitute, Memorial Sloan Kettering Cancer Center, New York, United States
  • 4 Barrow Neurological Institute (BNI), Phoenix, Arizona, United States
  • 5 Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, United States

The final, formatted version of the article will be published soon.

    Individuals with Down syndrome (DS) exhibit neurological deficits throughout life including the development of in Alzheimer's disease (AD) pathology and cognitive impairment.At the cellular level, dysregulation in neuronal gene expression is observed in postmortem human brain and mouse models of DS/AD. To date, RNA-sequencing (RNA-seq) analysis of hippocampal neuronal gene expression including the characterization of discrete circuit-based connectivity in DS remains a major knowledge gap. We postulate that spatially characterized hippocampal neurons display unique gene expression patterns due, in part, to dysfunction of the integrity of intrinsic circuitry. We combined laser capture microdissection to microisolate individual neuron populations with single population RNA-seq analysis to determine gene expression analysis of CA1 and CA3 pyramidal neurons and dentate gyrus granule cells located in the hippocampus, a region critical learning and memory and synaptic activity. The hippocampus exhibits agedependent neurodegeneration beginning at ~6 months of age in the Ts65Dn mouse model of DS/AD. Each population of excitatory hippocampal neurons exhibited unique gene expression alterations in Ts65Dn mice. Bioinformatic inquiry revealed unique vulnerabilities and differences with mechanistic implications coinciding with onset of degeneration in this model of DS/AD. These cell-type specific vulnerabilities may underlie degenerative endophenotypes suggesting precision medicine targeting of individual populations of neurons for rational therapeutic development.

    Keywords: alzhaimer disease, bioinformatics, Down Syndrome, Hippocampus, Laser capture microdissectio, RNA sequecing, selective vulnerability, Trisomy

    Received: 16 Dec 2024; Accepted: 30 Jan 2025.

    Copyright: © 2025 Alldred, Ibrahim, Pidikiti, Lee, Heguy, Chiosis, Mufson, Stutzmann and Ginsberg. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Stephen D Ginsberg, Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.