Cell-type-directed network-correcting combination therapy for Alzheimer’s disease. Yaqiao Li et al.
Description
We organized and computationally integrated a comprehensive single nucleus RNA-sequencing (snRNA-seq) dataset by combining published data from three independent studies ( Mathys et al 2019., Zhou et al. 2020, and Lau et al. 2020). This integrated analysis enhanced patient representation, effectively corrected batch/technical artifacts, and improved consistency in DEG detection efficiency across cell types, enabling robust and unbiased downstream drug target screening using these cell-type-specific DEG profiles as inputs. Single-nucleus RNA-sequencing analysis of the combination-treated (letrozole and irinotecan) and vehicle-treated mice confirmed that the combination therapy demonstrated beneficial effects transcriptomically, through increasing neuronal cell abundance, promoting neuroprotective functional pathways, and reversing disease-associated gene networks in a cell-type-specific manner.
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Steps to reproduce
We computationally integrated, using canonical correlation analysis algor three publicly available human snRNA-seq datasets from three independent sources. Both Mathys et al. and Zhou et al. studies were obtained from the Accelerating Medicines Partnership Alzheimer’s Disease Project (AMP-AD) Knowledge Portal (https://adknowledgeportal.org) under the Religious Order Study and Memory and Aging Project (ROSMAP). The Mathys et al. dataset is accessible through https://doi.org/10.7303/syn2580853. The Zhou et al. dataset is available under the study snRNAseqAD_TREM2 and is also accessible through https://doi.org/10.7303/syn21125841. Only individuals without TREM2 mutations were included in our integrated dataset. The third dataset by Lau et al. was obtained from Gene Expression Omnibus (GEO) under the accession number GSE157827. We standardized case and control classification across datasets using CERAD and Braak scores, excluding samples that did not meet both criteria for AD or control. The second file contains raw counts of snRNA-seq dataset from the combination and vehicle-treated mice. Information for sample conditions is provided as metadata excel file. For details regarding the experimental design, please see the STAR Methods of the manuscript.
Institutions
- University of California San Francisco