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

Overview

Journal Front Mol Neurosci

Specialty Molecular Biology

Date 2025 Mar 13

PMID 40078964

Authors

Melissa J Alldred

Kyrillos W Ibrahim

Harshitha Pidikiti

Sang Han Lee

Adriana Heguy

Gabriela Chiosis

Elliott J Mufson

Grace E Stutzmann

Stephen D Ginsberg

Affiliations

Soon will be listed here.

Abstract

Introduction: 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.

Methods: 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 for learning, memory, and synaptic activity.

Results: The hippocampus exhibits age-dependent 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.

Conclusions: These cell-type specific vulnerabilities may underlie degenerative endophenotypes suggesting precision medicine targeting of individual populations of neurons for rational therapeutic development.

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