Logan Brase, United States of America
Washington University in St Louis PsychiatryPresenter of 2 Presentations
MOLECULAR CHARACTERIZATION OF AUTOSOMAL DOMINANT AND SPORADIC ALZHEIMER DISEASE BRAINS LEVERAGING SINGLE-NUCLEI RNA-SEQUENCING
Abstract
Aims
AD has a substantial genetic, molecular and cellular heterogeneity associated with its etiology. We sought to investigate the glial and neuronal pathways affected by AD at a cell specific resolution. To do so, we generated single-nuclei RNA-seq (snRNA-seq) from the parietal cortex of Mendelian mutation carriers, sporadic AD and neuropath-free donors from the Knight-ADRC and Dominantly Inherited Alzheimer Network banks.
Methods
We generated snRNAseq (10X chemistry v3) for 18 APP and PSEN1 mutation carriers, 36 sporadic AD and 9 controls. 336,892 nuclei remained after QC for clustering and analyses (Figure 1). Our analytical approach is based on the identification of cellular states, their characterization and identification of genes associated with genetic strata.
Results
We identified a myriad of transcriptional states for the most representative brain cell-types (Figure 1) with distinguishing expression profiles (mean of 600 genes overexpressed; FDR<0.05). We identified that neuronal and glial cells have specific transcriptional states enriched in nuclei from brains with APP and PSEN1 mutations. For example, a microglia cell state specific for these brains shows overexpression of genes related to apoptosis, NOD like receptor signaling, Parkin-Ubiquitin Proteasomal system and protein processing in ER, while the astrocyte cell state specific for these carriers shows overexpression of genes related to the lysosomal and Brain-Derived Neurotrophic Factor signaling pathways.
Conclusions
We developed a unique molecular atlas to study the pathways dysregulated in AD. Our analyses indicate that in the backdrop of neuropath free and even sporadic AD brains, ADAD samples have distinctive cell states and altered pathways in neurons and glia.
LIVE DISCUSSION
