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Brain Behav Immun. 2019 Apr 11. pii: S0889-1591(18)30842-0. doi: 10.1016/j.bbi.2019.04.011. [Epub ahead of print]

Cerebral transcriptome analysis reveals age-dependent progression of neuroinflammation in P301S mutant tau transgenic male mice.

Author information

1
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Natural Products Research Center, Korea Institute of Science and Technology, Gangneung, Gangwon-do, Republic of Korea.
2
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
3
Department of Pharmacology, National University of Singapore, Singapore; Memory Aging and Cognition Centre, National University Health System, Singapore.
4
Saw Swee Hock School of Public Health, National University of Singapore, Singapore; Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, Singapore.
5
Department of Medicine, Yong Loo Lin School of Medicine, National University Health System, Singapore.
6
School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea.
7
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore; Neuroscience and Behavioral Disorders Program, Duke-NUS Medical School, Singapore; Neurobiology Programme, Life Sciences Institute, National University of Singapore, Singapore.
8
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea; Neurobiology Programme, Life Sciences Institute, National University of Singapore, Singapore. Electronic address: phstva@nus.edu.sg.

Abstract

Aggregation of the microtubule-associated protein, tau, can lead to neurofibrillary tangle formation in neurons and glia which is the hallmark of tauopathy. The cellular damage induced by the formation of neurofibrillary tangles leads to neuroinflammation and consecutive neuronal death. However, detailed observation of transcriptomic changes under tauopathy together with the comparison of age-dependent progression of neuroinflammatory gene expressions mediated by tau overexpression is required. Employing RNA sequencing on PS19 transgenic mice that overexpress human mutant tau harboring the P301S mutation, we have examined the effects of age-dependent tau overexpression on transcriptomic changes of immune and inflammatory responses in the cerebral cortex. Compared to age-matched wild type control, P301S transgenic mice exhibit significant transcriptomic alterations. We have observed age-dependent neuroinflammatory gene expression changes in both wild type and P301S transgenic mice where tau overexpression further promoted the expression of neuroinflammatory genes in 10-month old P301S transgenic mice. Moreover, functional gene network analyses (gene ontology and pathway enrichment) and prospective target protein interactions predicted the potential involvement of multiple immune and inflammatory pathways that may contribute to tau-mediated neuronal pathology. Our current study on P301S transgenic mice model revealed for the first time, the differences of gene expression patterns in both early and late stage of tau pathology in cerebral cortex. Our analyses also revealed that tau overexpression alone induces multiple inflammatory and immune transcriptomic changes and may provide a roadmap to elucidate the targets of anti-inflammatory therapeutic strategy focused on tau pathology and related neurodegenerative diseases.

KEYWORDS:

Neuroinflammation; P301S; PS19; RNA sequencing; Tauopathy; Transcriptome

PMID:
30980950
DOI:
10.1016/j.bbi.2019.04.011

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