Single Nucleus Transcriptome Data from Alzheimer’s Disease Mouse Models Yield New Insight into Pathophysiology

Article type: Research Article

Authors: Weller, Andrew E.^{a; *} | Ferraro, Thomas N.^{a; b} | Doyle, Glenn A.^a | Reiner, Benjamin C.^a | Crist, Richard C.^a | Berrettini, Wade H.^a

Affiliations: [a] Department of Psychiatry, Center for Neurobiology and Behavior, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA | [b] Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA

Correspondence: [*] Correspondence to: Andrew E. Weller, MD, 125S. 31st St., room 2208-2, Philadelphia, PA 19104, USA. Tel.: +1 215 898 6417; Fax: +1 215 573 2041; E-mail:andrew.weller@pennmedicine.upenn.edu.

Abstract: Background:5XFAD humanized mutant mice and Trem2 knockout (T2KO) mice are two mouse models relevant to the study of Alzheimer’s disease (AD)-related pathology. Objective:To determine hippocampal transcriptomic and polyadenylation site usage alterations caused by genetic mutations engineered in 5XFAD and T2KO mice. Methods:Employing a publicly available single-nucleus RNA sequencing dataset, we used Seurat and Sierra analytic programs to identify differentially expressed genes (DEGs) and differential transcript usage (DTU), respectively, in hippocampal cell types from each of the two mouse models. We analyzed cell type-specific DEGs further using Ingenuity Pathway Analysis (IPA). Results:We identified several DEGs in both neuronal and glial cell subtypes in comparisons of wild type (WT) versus 5XFAD and WT versus T2KO mice, including Ttr, Fth1, Pcsk1n, Malat1, Rpl37, Rtn1, Sepw1, Uba52, Mbp, Arl6ip5, Gm26917, Vwa1, and Pgrmc1. We also observed DTU in common between the two comparisons in neuronal and glial subtypes, specifically in the genes Prnp, Rbm4b, Pnisr, Opcml, Cpne7, Adgrb1, Gabarapl2, Ubb, Ndfip1, Car11, and Stmn4. IPA identified three statistically significant canonical pathways that appeared in multiple cell types and that overlapped between 5XFAD and T2KO comparisons to WT, including ‘FXR/RXR Activation’, ‘LXR/RXR Activation’, and ‘Acute Phase Response Signaling’. Conclusion:DEG, DTU, and IPA findings, derived from two different mouse models of AD, highlight the importance of energy imbalance and inflammatory processes in specific hippocampal cell types, including subtypes of neurons and glial cells, in the development of AD-related pathology. Additional studies are needed to further characterize these findings.

Keywords: Alzheimer’s disease, animal disease models, gene expression profiling, knockout mice, mice, polyadenylation, RNA-seq

DOI: 10.3233/JAD-220391

Journal: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1233-1247, 2022