Multi‐tissue profiling of RNA and DNA‐methylation signatures of progressive tau neuropathology in tau transgenic mice. (20th December 2022)

• Record Type: Journal Article
• Authors: Kulkarni, Ameya S; Ideozu, Justin; Vasanthakumar, Aparna; Ammar, Areej; Murphy, Erin; Asque, Elizabeth; Plaas, Christian; Klein, Corinna; Ried, Janina S; Barghorn, Stefan; Gasparini, Laura
• Is Part Of: Alzheimer's & dementia. Volume 18(2022)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-20
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.060736
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Intracellular abnormal aggregation of hyperphosphorylated tau protein is a neuropathological hallmark associated with Alzheimer's Disease (AD). The insoluble tau aggregates called neurofibrillary tangles lead to microtubule dysfunction and neurodegeneration with AD progression. The TG4510 transgenic mice overexpressing the P301L mutant human tau protein exhibit region‐specific tau inclusions, brain atrophy, and behavioral deficits, thereby serving as a widely used animal model of tauopathy in AD. This study aims to characterize the tissue‐specific transcriptomic and epigenomic signatures of progressive tau pathology in TG4510 mice as well as investigate the correlation of brain and blood expression and epigenomic changes. Method: Using UMI‐based bulk RNA‐Sequencing and Reduced‐representation Bisulfite Sequencing (RRBS), we profiled the gene expression and DNA‐methylation changes respectively, in the cortex, hippocampus, cerebellum and pre‐sacrifice and terminal whole blood between three age groups (2‐3 months, 6‐7 months, 8‐9 months old; N=20/tissue/group) of male and female TG4510 mice. Result: The cortex and hippocampus show the largest transcriptional differences between mice, recapitulating phenotype differences with loss of neurotransmission and increased inflammation in these tissues. Systems‐level co‐expression analysis reveals common gene modules in immune system, behaviour and cognition and ECM/synaptic pathways between cortex/hippocampus and blood. Furthermore, the genes correlated between brain regions and blood in these mice were prioritized as potential biomarkers of tau pathology, which can be further validated in preclinical animal models and ultimately human studies. Conclusion: This study serves as one of the first evidence of multiomic molecular underpinnings in a tauopathy mouse model providing potential novel targets and biomarkers of progressive tau pathology in AD. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.