Divergent phosphorylation pattern of tau in P301L tau transgenic mice

Deters, Natasha, Ittner, Lars M. and Gotz, Jurgen (2008) Divergent phosphorylation pattern of tau in P301L tau transgenic mice. European Journal of Neuroscience, 28 1: 137-147. doi:10.1111/j.1460-9568.2008.06318.x

Author Deters, Natasha
Ittner, Lars M.
Gotz, Jurgen
Title Divergent phosphorylation pattern of tau in P301L tau transgenic mice
Journal name European Journal of Neuroscience   Check publisher's open access policy
ISSN 0953-816X
Publication date 2008
Sub-type Article (original research)
DOI 10.1111/j.1460-9568.2008.06318.x
Open Access Status
Volume 28
Issue 1
Start page 137
End page 147
Total pages 11
Place of publication Chichester, West Sussex, United Kingdom
Publisher Wiley-Blackwell
Language eng
Abstract Aggregates of hyperphosphorylated tau are prominent in brains of patients with Alzheimer's disease or frontotemporal dementia (FTD). They have been reproduced in animal models following the identification of tau mutations in familial cases of FTD. This includes our previously generated transgenic model, pR5, which expresses FTD (P301L) mutant tau in neurons. The mice are characterized by tau aggregation including tangle (NFT) formation, memory impairment and mitochondrial dysfunction. In 8-month- old mice, S422 phosphorylation of tau is linked to NFT formation, however, a detailed analysis of tau solubility, phosphorylation and aggregation has not been done nor have the mice been monitored until a high age. Here, we undertook an analysis by immunohistochemistry, Gallyas impregnation and Western blotting of brains from 3 month- up to 20 month-old mice. NFTs first appeared at 6 months in the amygdala, followed by the CA1 region of the hippocampus. As the mice get older, the solubility of tau is decreased as determined by sequential extractions. Histological analysis revealed increased phosphorylation at the AT180, AT270 and 12E8 epitopes with ageing. The numbers of AT8-positive neurons increased from 3 to 6 months old. However, whereas S422 appeared only late and concomitantly with NFT formation, the only neurons left with AT8-reactivity at 20 months were those that had undergone NFT formation. As hyperphosphorylated tau continued to accumulate, the lack of AT8-reactivity suggests regulatory mechanisms in specifically dephosphorylating the AT8 epitope in the remaining neurons. Thus, differential regulation of phosphorylation is important for NFT formation in neurodegenerative diseases with tau pathology.
Keyword Alzheimer's disease
At8 epitope
Frontotemporal dementia
Neurofibrillary tangles
Ps422 epitope
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
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