Increased misfolding and truncation of tau in APP/PSI/tau transgenic mice compared to mutant tau mice

Neurofibrillary degeneration in transgenic models of tauopathies has been observed to be enhanced when these models are crossed with transgenic models developing an A beta pathology. The mechanisms leading to this enhanced tau pathology are not well understood. We have performed a detailed analysis of tau misprocessing in a new transgenic mouse model combining APP, PSI and tau mutations (5xFAD x Tg30 mice) by comparison with littermates expressing only a FTD mutant tau (Tg30 mice). These 5xFAD x Tg30 mice showed a more severe deficient motor phenotype than Tg30 mice and developed with age a dramatically accelerated NFT load in the brain compared to Tg30 mice. Insoluble tau in 5xFAD x Tg30 mice compared to insoluble tau in Tg30 mice showed increased phosphorylation, enhanced misfolding and truncation changes mimicking more closely the post-translational changes characteristic of PHF-tau in Alzheimer's disease. Endogenous wild-type mouse tau was recruited at much higher levels in insoluble tau in 5xFAD x Tg30 than in Tg30 mice. Extracellular amyloid load, A beta 40 and A beta 42, beta-CTFs and beta-CTF phosphorylation levels were lower in 5xFAD x Tg30 mice than in 5xFAD mice. Despite this reduction of A beta, a significant hippocampal neuronal loss was observed in 5xFAD x Tg30 but not in 5xFAD mice indicating its closer association with increased tau pathology. This 5xFAD x Tg30 model thus mimics more faithfully tau pathology and neuronal loss observed in AD and suggests that additional posttranslational changes in tau and self-recruitment of endogenous tau drive the enhanced tau pathology developing in the presence of A beta pathology. (C) 2013 Elsevier Inc All rights reserved.