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Basic Science and Pathogenesis.

Tra-My Vu1, Klarissa Leduc1, Martin Newton1

  • 1Université de Montréal, Montréal, QC, Canada.

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Amyloid-beta (Aß) oligomers cause neuronal loss in the hippocampus, a key brain region for memory. This study reveals early molecular changes in brain cells, potentially identifying new Alzheimer

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genomics

Background:

  • Alzheimer's disease (AD) is characterized by amyloid-beta (Aß) oligomer and neurofibrillary tangle accumulation.
  • Aß oligomers precede clinical AD symptoms by 10-15 years, impacting hippocampal synaptic and neuronal function.
  • The hippocampus, crucial for memory, is affected early in AD pathogenesis.

Purpose of the Study:

  • To investigate the impact of Aß oligomers on distinct hippocampal cell types.
  • To profile molecular changes using single-nucleus transcriptomic and chromatin accessibility analysis in a rat model.

Main Methods:

  • Daily injection of Aß oligomers into the rat hippocampus for 0, 2, 4, or 6 days.
  • Laser microdissection of nuclei from specific hippocampal cell types (neurons, astrocytes, oligodendrocytes, pericytes, endothelial cells, microglia).
  • Simultaneous single-nucleus RNA-sequencing and single-nucleus ATAC-sequencing (10xGenomics).

Main Results:

  • Observed neuronal loss in the dentate gyrus granular layer following Aß oligomer injection.
  • Significant Aß accumulation in the hippocampus after 6 days of consecutive injection.
  • Identified distinct cell clusters with altered gene expression profiles over time.

Conclusions:

  • This research elucidates specific gene expression and epigenetic alterations induced by Aß oligomers in hippocampal cells.
  • Findings provide insights into early AD progression at a cellular level.
  • Potential to identify novel therapeutic targets for early-stage Alzheimer's disease.