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CNS cell type-specific gene profiling of P301S tau transgenic mice identifies genes dysregulated by progressive tau accumulation

Abstract

The microtubule-associated protein tau undergoes aberrant modification resulting in insoluble brain deposits in various neurodegenerative diseases, including frontotemporal dementia (FTD), progressive supranuclear palsy, and corticobasal degeneration. Tau aggregates can form in different cell types of the central nervous system (CNS) but are most prevalent in neurons. We have previously recapitulated aspects of human FTD in mouse models by overexpressing mutant human tau in CNS neurons, including a P301S tau variant in TAU58/2 mice, characterized by early-onset and progressive behavioral deficits and FTD-like neuropathology. The molecular mechanisms underlying the functional deficits of TAU58/2 mice remain mostly elusive. Here, we employed functional genomics (i.e. RNAseq) to determine differentially expressed genes in young and aged TAU58/2 mice to identify alterations in cellular processes that may contribute to neuropathy. We identified genes in cortical brain samples differentially regulated between young and old TAU58/2 mice relative to nontransgenic littermates and by comparative analysis with a dataset of CNS cell type-specific genes expressed in nontransgenic mice. Most differentially-regulated genes had known or putative roles in neurons and included presynaptic and excitatory genes. Specifically, we observed changes in presynaptic factors, glutamatergic signaling, and protein scaffolding. Moreover, in the aged mice, expression levels of several genes whose expression was annotated to occur in other brain cell types were altered. Immunoblotting and immunostaining of brain samples from the TAU58/2 mice confirmed altered expression and localization of identified and network-linked proteins. Our results have revealed genes dysregulated by progressive tau accumulation in an FTD mouse model.

Type Journal
ISBN 1083-351X (Electronic) 0021-9258 (Linking)
Authors Ke, Y. D.; Chan, G.; Stefanoska, K.; Au, C.; Bi, M.; Muller, J.; Przybyla, M.; Feiten, A.; Prikas, E.; Halliday, G. M.; Piguet, O.; Kiernan, M. C.; Kassiou, M.; Hodges, J. R.; Loy, C. T.; Mattick, J. S.; Ittner, A.; Kril, J. J.; Sutherland, G. T.; Ittner, L. M.
Responsible Garvan Author (missing name)
Publisher Name JOURNAL OF BIOLOGICAL CHEMISTRY
Published Date 2019-09-20
Published Volume 294
Published Issue 38
Published Pages 14149-14162
Status Published in-print
DOI 10.1074/jbc.RA118.005263
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/31366728