Transcriptome and Translatome Regulation of Pathogenesis in Alzheimer’s Disease Model Mice

Article type: Research Article

Authors: Eastman, Guillermo^{a; b} | Sharlow, Elizabeth R.^c | Lazo, John S.^{c; d} | Bloom, George S.^{b; e; f; *} | Sotelo-Silveira, José R.^{a; g; *}

Affiliations: [a] Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable, Ministerio de Educación y Cultura, Montevideo, Uruguay | [b] Department of Biology, University of Virginia, Charlottesville, VA, USA | [c] Department of Pharmacology, University of Virginia, Charlottesville, VA, USA | [d] Department of Chemistry, University of Virginia, Charlottesville, VA, USA | [e] Department of Cell Biology, University of Virginia, Charlottesville, VA, USA | [f] Department of Neuroscience, University of Virginia, Charlottesville, VA, USA | [g] Sección Biología Celular, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay

Correspondence: [*] Correspondence to: José R. Sotelo-Silveira, Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable, Av. Italia 3318, 11600, Montevideo, Uruguay. Tel.: +598 2487 1616 173; E-mail: [email protected] or E-mail: [email protected] and George S. Bloom, Department of Biology, University of Virginia, PO Box 400328, Charlottesville, VA 22904-4328, USA. Tel.: +1 434 243 3543; E-mail: [email protected].

Abstract: Background:Defining cellular mechanisms that drive Alzheimer’s disease (AD) pathogenesis and progression will be aided by studies defining how gene expression patterns change during pre-symptomatic AD and ensuing periods of declining cognition. Previous studies have emphasized changes in transcriptome, but not translatome regulation, leaving the ultimate results of gene expression alterations relatively unexplored in the context of AD. Objective:To identify genes whose expression might be regulated at the transcriptome and translatome levels in AD, we analyzed gene expression in cerebral cortex of two AD model mouse strains, CVN (APPSwDI;NOS2 -/- ) and Tg2576 (APPSw), and their companion wild type (WT) strains at 6 months of age by tandem RNA-Seq and Ribo-Seq (ribosome profiling). Methods:Identical starting pools of bulk RNA were used for RNA-Seq and Ribo-Seq. Differential gene expression analysis was performed at the transcriptome, translatome, and translational efficiency levels. Regulated genes were functionally evaluated by gene ontology tools. Results:Compared to WT mice, AD model mice had similar levels of transcriptome regulation, but differences in translatome regulation. A microglial signature associated with early stages of Aβ accumulation was upregulated at both levels in CVN mice. Although the two mice strains did not share many regulated genes, they showed common regulated pathways related to AβPP metabolism associated with neurotoxicity and neuroprotection. Conclusion:This work represents the first genome-wide study of brain translatome regulation in animal models of AD and provides evidence of a tight and early translatome regulation of gene expression controlling the balance between neuroprotective and neurodegenerative processes in brain.

Keywords: Alzheimer’s disease, amyloid, microglia, RNA-Seq, mRNA translation, transcriptome regulation

DOI: 10.3233/JAD-215357

Journal: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 365-386, 2022