Enhanced Neurofibrillary Degeneration in Transgenic Mice Expressing Mutant Tau and APP

Lewis, Jada; Dickson, Dennis W.; Lin, Weili; Chisholm, Louise; Corral, Anthony; Jones, Graham L.; Yen, Shu‐Hui; Sahara, Naruhiko; Skipper, Lisa; Yager, Debra; Eckman, Chris; Hardy, John; Hutton, Mike; McGowan, Eileen

doi:10.1126/science.1058189

Cited by 1,392 publications

(928 citation statements)

References 35 publications

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“…A role for Ah in neurofibrillary degeneration is also supported by recent findings showing that coexpression of human mutant tau and APP in the mouse brain results in increased NFT formation, whereas amyloid deposition remains essentially unaltered (Lewis et al, 2001). Moreover, intracerebral injection of fibrillar Ah42 in P301L mutant tau transgenic (Tg) mice caused a fivefold increase in the number of NFT, favoring the hypothesis that fibrillar Ah can accelerate NFT formation in vivo (Gotz et al, 2001).…”

Section: Introductionsupporting

confidence: 59%

Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice

Ribé

Pérez

Puig

et al. 2005

Neurobiology of Disease

152

115

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Even though the idea that amyloid B peptide accumulation is the primary event in the pathogenesis of Alzheimer's disease has become the leading hypothesis, the causal link between aberrant amyloid precursor protein processing and tau alterations in this type of dementia remains controversial. We further investigated the role of B-amyloid production/deposition in tau pathology and neuronal cell death in the mouse brain by crossing Tg2576 and VLW lines expressing human mutant amyloid precursor protein and human mutant tau, respectively. The resulting double transgenic mice showed enhanced amyloid deposition accompanied by neurofibrillary degeneration and overt neuronal loss in selectively vulnerable brain limbic areas. These findings challenge the idea that tau pathology in Alzheimer's disease is merely a downstream effect of amyloid production/deposition and suggest that reciprocal interactions between B-amyloid and tau alterations may take place in vivo. D

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Section: Introductionsupporting

confidence: 59%

Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice

Ribé

Pérez

Puig

et al. 2005

Neurobiology of Disease

152

115

View full text Add to dashboard Cite

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“…Importantly, Aβ immunotherapy did not reverse late, well-established tau aggregation, pointing out the importance of preventing this pathology very early before synaptic and neuronal losses have occurred (see below). These and other studies [36,37] suggest that, at least in the mouse model, Aβ deposition precedes and exacerbates NFT formation.…”

Section: Potential Uses Of An Aβ Imaging Agentsupporting

confidence: 61%

Impact of amyloid imaging on drug development in Alzheimer's disease

Mathis

Lopresti

Klunk

2007

Nuclear Medicine and Biology

111

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Imaging agents capable of assessing amyloid-beta (Aβ) content in vivo in the brains of Alzheimer's disease (AD) subjects likely will be important as diagnostic agents to detect Aβ plaques in the brain, to help test the amyloid cascade hypothesis of AD, and as an aid to assess the efficacy of anti-amyloid therapeutics currently under development and in clinical trials. Positron emission tomography (PET) imaging studies of amyloid deposition in human subjects with several Aβ imaging agents are currently underway. We reported the first PET studies of the carbon-11-labeled thioflavin-T derivative Pittsburgh Compound B ([ 11 C]PiB) in 2004, and this work has subsequently been extended to include a variety of subject groups including AD, mild cognitive impairment (MCI), and healthy controls. The ability to quantify regional Aβ plaque load in the brains of living human subjects has provided a means to begin to apply this technology as a diagnostic agent to detect regional concentrations of Aβ plaques and as a surrogate marker of therapeutic efficacy in anti-amyloid drug trials.

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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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Enhanced Neurofibrillary Degeneration in Transgenic Mice Expressing Mutant Tau and APP

Cited by 1,392 publications

References 35 publications

Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice

Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice

Impact of amyloid imaging on drug development in Alzheimer's disease

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

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