Increased misfolding and truncation of tau in APP/PS1/tau transgenic mice compared to mutant tau mice

Abstract

Neurofibrillary degeneration in transgenic models of tauopathies has been observed to be enhanced when these models are crossed with transgenic models developing an Aß 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, PS1 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 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, Aß40 and Aß42, ß-CTFs and ß-CTFs phosphorylation levels were lower in 5xFAD x Tg30 mice than in 5xFAD mice. Despite this reduction of Aß, 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 post-translational changes in tau and self-recruitment of endogenous tau drive the enhanced tau pathology developing in presence of Aß pathology.

Activation of peroxisome proliferator-activated receptor α stimulates ADAM10-mediated proteolysis of APP

“…In addition, 5XFAD mice null for PPARα displayed significantly shorter life spans (by ∼2 mo) compared with their traditional 5XFAD littermates. Although there is no definitive correlation between Aβ and lifespan per se, there is evidence that increased Aβ burden induces early mortality in mice (24) and lower organisms (25). There is also evidence that elevated Aβ levels are associated with reduced lifespan in the human disease (26).…”

Combination of PKCε Activation and PTP1B Inhibition Effectively Suppresses Aβ-Induced GSK-3β Activation and Tau Phosphorylation

“…Several lines of evidence have pointed to the relation between Aβ and tau in the pathogenesis of AD; Aβ induces tau phosphorylation, accelerates NFT formation, and enhances tau pathology, or misfolded Aβ induces prion-like misfolded tau oligomers [13,14,30]. Tau aggregation is shown to precede β-amyloid deposits by about 30 years [31,32].…”

“…Aβ induces tau phosphorylation, enhances tau pathology, and accelerates NFT formation [10][11][12][13][14][15]. Tau is phosphorylated by a variety of serine/threonine protein kinases such as GSK-3β, cyclin-dependent kinase 5 (CDK5), extracellular-signalregulated kinase 2 (ERK2), S6 kinase, microtubule-affinityregulating kinase (MARK), SAD kinase, and PKA or Src family kinases such as fyn and c-Abl [16][17][18].…”

The Prion-Like Properties of Amyloid-β Assemblies: Implications for Alzheimer's Disease

“…Although the degree of tauopathy correlates more strongly with cognitive decline than does the buildup of Ab (Giannakopoulos et al 2003), extant evidence indicates that in AD (Hardy and Selkoe 2002;Holtzman et al 2011;Nelson et al 2012) and in genetically modified mice (Götz et al 2001;Lewis et al 2001;Bolmont et al 2007;Héraud et al 2014;Stancu et al 2014;Vasconcelos et al 2016), tauopathy is downstream from Ab proteopathy. Moreover, the genetic causes of autosomal dominant AD identified so far all affect Ab by enhancing its release from the Ab-precursor protein (APP) or its tendency to self-aggregate (Hardyand Selkoe 2002).…”