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Early-onset Axonal Pathology in a Novel P301S-Tau Transgenic Mouse Model of Frontotemporal Dementia

van Ersel, Janet and Stevens, Claire H and Przybyla, Magdalena and Gladbach, Amadeus and Stefanoska, Kristie and Chan, Chesed and Xin, Kai and Ong, Wei Yi and Hodges, John R and Sutherland, Greg T and Kril, Jilian J and Abramowski, Dorothee and Staufenbiel, Matthias and Halliday, Glenda M and Ittner, Lars M (2015) Early-onset Axonal Pathology in a Novel P301S-Tau Transgenic Mouse Model of Frontotemporal Dementia. Neuropathology Appl Neurobiol..

Abstract

Tau becomes hyperphosphorylated in Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD), resulting in functional deficits of neurons, neurofibrillary tangle (NFT) formation and eventually dementia. Expression of human tau carrying pathogenic mutations identified in familial FTLD with tau pathology (FTLD-tau) in the brains of transgenic mice has produced different lines that recapitulate various aspects of the human disease. These models have significantly contributed to understanding underlying disease mechanisms. Here we report a novel P301S mutant tau transgenic mouse line, Tau58/2 with early-onset motor deficits and a pronounced axonal pathology. While progressive tau phosphorylation resulted in NFT formation in aged mice, frequent axonal swellings were already present in young Tau58/2 mice, coinciding with early onset of motor deficits. These axonal swellings stained intensively for neurofilament (NF), but were largely negative for transgenic human tau. Interestingly, activated microglia were found in close proximity to cell bodies of neurons harboring transgenic tau, but not associated with NF-positive axonal swellings, suggesting that the latter did not induce a cellular tissue response. Our findings are in line with the view that early tau pathology induces functional deficits of neurons that in turn result in NF pathology. This appears to be a reaction specific to tau, since we observed similar changes in a range of FTLD-tau subtypes, but not in FTLD with TDP-43 inclusions (FTLD-TDP). Taken together, we established a new P301S tau transgenic mouse line, which recapitulates aspects of human FTLD-tau and AD pathology, and will become instrumental in studying disease mechanisms and testing novel therapeutic approaches in the future.

Item Type: Article
Date Deposited: 04 May 2016 23:45
Last Modified: 04 May 2016 23:45
URI: https://oak.novartis.com/id/eprint/24273

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