INTERNATIONAL ASSOCIATION OF BIOMEDICAL SCIENCES

  “ IABS Forum-2023 ” December 2023
ABSTRACT

Cell Specific Early Dysfunctional Gene Clusters in the APPNL-G-F (APPKI) Alzheimer’s Model

Brian Giles1, Surjyadipta Bhattacharjee1, Jeff Ji1, Marianne Schultzberg2, Nicolas G Bazan1

1Neuroscience Center of Excellence, School of Medicine, LSU Health New Orleans, New Orleans, LA 70122, USA;
2Karolinska Institutet, Dept of Neurobiology, Care Sciences & Society, Stockholm, Sweden

  ABSTRACT

 Alzheimer’s Disease (AD) occurrence is expected to triple by the year 2060. Due to a lack of the understanding of causative mechanisms we are devoid of effective therapies. We have explored the hippocampus and cortex of the 2-month old APPNL-G-F (APPKI) using 10× Genomics Chromium Single Cell Multiome Assay for Transposase Accessible Chromatin (ATAC) + Gene Expression (GEX) to define at the transcriptome level, cell specific alterations in immune, lipid , metabolic and neurodevelopment related gene clusters. Additionally, we have assessed DNA-methylation to uncover related CpG islands and gene promoters.
 The APPKI is an AD model with three additive/synergistic mutations that show typical Amyloid- β (Aβ) pathology and neuroinflammation. The hippocampus and cortex of the right hemisphere were flash-frozen in liquid nitrogen. Nuclei isolation was done by the Chromium Nuclei isolation kit and data generation following 10× Single Cell Muiltiome workflow and analysis performed using R-based packages: Seurat and Signac.
 We found a) Inflammatory gene expression changes in C1qa/b/c, Cox6c, Cox7c, and Cox8a; b) Chromatin accessibility modifications in DNA corresponding with Nr3c1, Jund, Spib, Meox1, and Lhx5; c) Prominent methylation in regions correlated with Necdin: and d) epigenomic landscape , senescence gene programming, autophagy, extracellular matrix and inflammaging changing. Overall, the APP KI model allowed us to identify cell specific early dysfunctional gene clusters.

 ACKNOWLEDGMENTS

   Research support from the EENT Foundation,New Orleans (NGB).

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