Amyloid β accelerates phosphorylation of tau and neurofibrillary tangle formation in an amyloid precursor protein and tau double‐transgenic mouse model

Seino, Yusuke; Kawarabayashi, Tatsuhiko; Wakasaya, Yasuhito; Watanabe, Mitsunori; Takamura, Ayumi; Yamamoto-Watanabe, Yukiko; Kurata, Tomoko; Abe, Kōji; Ikeda, Masaki; Westaway, David; Murakami, Tetsuro; George-Hyslop, Peter St; Matsubara, Etsuro; Shoji, Mikio

doi:10.1002/jnr.22516

Cited by 27 publications

(19 citation statements)

References 32 publications

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“…hTau‐A152T was more detrimental in this regard than hTau‐WT. This functional synergism with hAPP/Aβ may be a special, if not unique, feature of the A152T substitution, as it was not observed in mice co‐expressing hAPP/Aβ with hTau bearing FTDP‐17 mutations 89, 90, 91, 92, 93. Thus, besides increasing hTau levels, the A152T substitution appears to enhance tau's ability to support network hyperexcitability, a mechanism through which it could promote excitotoxicity and neurodegeneration.…”

Section: Discussionmentioning

confidence: 95%

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

et al. 2016

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A152T‐variant human tau (hTau‐A152T) increases risk for tauopathies, including Alzheimer's disease. Comparing mice with regulatable expression of hTau‐A152T or wild‐type hTau (hTau‐WT), we find age‐dependent neuronal loss, cognitive impairments, and spontaneous nonconvulsive epileptiform activity primarily in hTau‐A152T mice. However, overexpression of either hTau species enhances neuronal responses to electrical stimulation of synaptic inputs and to an epileptogenic chemical. hTau‐A152T mice have higher hTau protein/mRNA ratios in brain, suggesting that A152T increases production or decreases clearance of hTau protein. Despite their functional abnormalities, aging hTau‐A152T mice show no evidence for accumulation of insoluble tau aggregates, suggesting that their dysfunctions are caused by soluble tau. In human amyloid precursor protein (hAPP) transgenic mice, co‐expression of hTau‐A152T enhances risk of early death and epileptic activity, suggesting copathogenic interactions between hTau‐A152T and amyloid‐β peptides or other hAPP metabolites. Thus, the A152T substitution may augment risk for neurodegenerative diseases by increasing hTau protein levels, promoting network hyperexcitability, and synergizing with the adverse effects of other pathogenic factors.

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Section: Discussionmentioning

confidence: 95%

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

et al. 2016

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“…Double transgenic mice expressing mutants APP and tau proteins develop an enhanced tau pathology (Bolmont et al, 2007;Hurtado et al, 2010;Lewis et al, 2001;Paulson et al, 2008;Perez et al, 2005;Seino et al, 2010;Terwel et al, 2008). The enhancement of tauopathy by Aß accumulation in APP/tau models has been described in some models as slow, developing with aging, and relatively modest (Paulson et al, 2008;Perez et al, 2005;Seino et al, 2010;Terwel et al, 2008). The mechanisms of worsened tau pathology in these APP/tau models are however not well understood, and potential additional misprocessing of tau in these APP/tau models compared to tau in FTD tau models has not been clarified.…”

Section: Introductionmentioning

confidence: 99%

“…Injection of Aß (Gotz et al, 2001) or of Aβ-containing brain extract from APP mice (Bolmont et al, 2007) was reported to increase NFT formation in mutant P301L tau mice. Double transgenic mice expressing mutants APP and tau proteins develop an enhanced tau pathology (Bolmont et al, 2007;Hurtado et al, 2010;Lewis et al, 2001;Paulson et al, 2008;Perez et al, 2005;Seino et al, 2010;Terwel et al, 2008). The enhancement of tauopathy by Aß accumulation in APP/tau models has been described in some models as slow, developing with aging, and relatively modest (Paulson et al, 2008;Perez et al, 2005;Seino et al, 2010;Terwel et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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

Héraud

Goufak

Ando

et al. 2014

Neurobiology of Disease

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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.

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“…Although AT8-immunopositive tau has been observed in other APP-only mouse models of AD primarily around cortical neuritic plaques (37–39), we sought to confirm the presence of hyperphosphorylated and aggregated tau in CVN-AD brain (Fig. 3).…”

Section: Resultsmentioning

confidence: 99%

mNos2Deletion and HumanNOS2Replacement in Alzheimer Disease Models

Colton

Wilson

Everhart

et al. 2014

J Neuropathol Exp Neurol

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Understanding the pathophysiological mechanisms underlying Alzheimer disease (AD) relies on knowledge of disease onset and the sequence of development of brain pathologies. We present a comprehensive analysis of early and progressive changes in a mouse model that demonstrates a full spectrum of characteristic AD-like pathologies. This model demonstrates an altered immune redox state reminiscent of the human disease and capitalizes on data indicating critical differences between human and mouse immune responses, particularly in nitric oxide (NO) levels produced by immune activation of the NOS2 gene. Using the APPSwDI+/+/mNos2−/− (CVN-AD) mouse strain, we show a sequence of pathological events leading to neurodegeneration that include pathologically hyperphosphorylated tau in the perforant pathway at 6 weeks of age progressing to insoluble tau, the early appearance of β-amyloid peptides in perivascular deposits around blood vessels in brain regions known to be vulnerable in AD and progression to damage and overt loss in select vulnerable neuronal populations in these regions. The role of species differences between hNOS2 and mNos2 was supported by generating mice in which the human NOS2 gene replaced mNos2. When crossed to CVN-AD mice, pathological characteristics of this new strain (APPSwDI+/−/huNOS2t +/+g/mNos2−/−) mimicked the pathological phenotypes found in the CVN-AD strain.

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Amyloid β accelerates phosphorylation of tau and neurofibrillary tangle formation in an amyloid precursor protein and tau double‐transgenic mouse model

Cited by 27 publications

References 32 publications

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

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

mNos2Deletion and HumanNOS2Replacement in Alzheimer Disease Models

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