Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein

Lewis, Jada; McGowan, Eileen; Rockwood, Julia M.; Melrose, Heather L.; Nacharaju, Parimala; Slegtenhorst, Marjon van; Gwinn‐Hardy, Katrina; Murphy, Michael P.; Baker, Matt; Yu, Xin; Duff, Karen; Hardy, John; Corral, Anthony; Lin, Wen Lang; Yen, Shu Hui; Dickson, Dennis W.; Davies, Peter; Hutton, Mike

doi:10.1038/78078

Cited by 1,225 publications

(1,149 citation statements)

References 21 publications

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“…Oxidative damage to nucleic acids is also increased in these mice, as measured by immunohistochemistry for 8-OHdG. Levels of oxidative damage in CNS tissue have not yet been reported for a P301 tau transgenic mouse that develops NFTs primarily in spinal cord [71], nor for a model of P301 tau conditional expression that develops NFTs in forebrain [72]. A transgenic mouse expressing mutant APP, PS1, and tau recently has been developed as a more "complete" model of AD pathologic changes, developing both Aβ plaques and NFTs [73,74].…”

Section: Transgenic Micementioning

confidence: 93%

Free radical-mediated damage to brain in Alzheimer's disease and its transgenic mouse models

Sonnen¹,

Breitner²,

Lovell³

et al. 2008

Free Radical Biology and Medicine

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Section: Transgenic Micementioning

confidence: 93%

Free radical-mediated damage to brain in Alzheimer's disease and its transgenic mouse models

Sonnen¹,

Breitner²,

Lovell³

et al. 2008

Free Radical Biology and Medicine

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“…Despite the robust amyloid deposition observed in APP and PSAPP transgenic mice and evidence for progressive synaptic degeneration and dysfunction, none of these models show neuron loss or formation of intraneuronal fibrillary tangles. On the other hand, mouse models expressing wild type or mutant MAPT gene have been generated that recapitulate most of the features of human neurofibrillary pathology and significant neuronal loss ( [4,136,205,263]). Further crossings among AD transgenic models have allowed to reach the conclusion that, although a mouse model that recapitulates all aspects of AD has yet to be obtained, amyloid deposition can accelerate or initiate the formation of neurofibrillary tangles while MAPT accumulation or other secondary events initiate neurodegeneration ([158,177,176]).…”

Section: Animal Models Of Alzheimer's Diseasementioning

confidence: 99%

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Vegeto

Benedusi

Maggi

2008

Frontiers in Neuroendocrinology

273

206

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a b s t r a c tRecent studies highlight the prominent role played by estrogens in protecting the central nervous system (CNS) against the noxious consequences of a chronic inflammatory reaction. The neurodegenerative process of several CNS diseases, including Multiple Sclerosis, Alzheimer's and Parkinson's Diseases, is associated with the activation of microglia cells, which drive the resident inflammatory response. Chronically stimulated during neurodegeneration, microglia cells are thought to provide detrimental effects on surrounding neurons. The inhibitory activity of estrogens on neuroinflammation and specifically on microglia might thus be considered as a beneficial therapeutic opportunity for delaying the onset or progression of neurodegenerative diseases; in addition, understanding the peculiar activity of this female hormone on inflammatory signalling pathways will possibly lead to the development of selected anti-inflammatory molecules. This review summarises the evidence for the involvement of microglia in neuroinflammation and the anti-inflammatory activity played by estrogens specifically in microglia.

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“…P301L tau has been used in a broad range of experimental model systems to study tau pathology. The most successful models of NFTs in rodents used this disease-related form of tau (Lewis et al, 2000) or a closely related mutation, P301S (Allen et al, 2002). In both of these models, transgenic mice develop profound motor dysfunction as early as 4 months of age, as well as NFTs and neuronal loss in the spinal cord and brain.…”

mentioning

confidence: 99%

Tau gene transfer, but not alpha-synuclein, induces both progressive dopamine neuron degeneration and rotational behavior in the rat

Klein

Dayton

Lin

et al. 2005

Neurobiology of Disease

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Using a viral vector for mutant (P301L) tau, we studied the effects of gene transfer to the rat substantia nigra in terms of structural and functional properties of dopaminergic neurons. The mutant tau vector caused progressive loss of pars compacta dopaminergic neurons over time, reduced striatal dopamine content, and amphetamine-stimulated rotational behavior consistent with a specific lesion effect. In addition, structural studies demonstrated neurofibrillary tangles and neuritic pathology. Wild-type tau had similar effects on neuronal loss and rotational behavior. In contrast, mutant α-synuclein vectors did not induce rotational behavior, although α-synuclein filaments formed in nigrostriatal axons. Dopamine neuron function is affected by tau gene transfer and appears to be more susceptible to tau-rather than α-synuclein-related damage in this model. Both tau and α-synuclein are important for substantia nigra neurodegeneration models in rats, further indicating their potential as therapeutic targets for human diseases involving loss of dopamine neurons. KeywordsAdeno-associated virus; α-Synuclein; Neurodegeneration; Neurofibrillary tangles; Substantia nigra; Tau Deposits of the microtubule-associated protein tau in the form of neurofibrillary tangles (NFTs) are characteristic of many neurodegenerative diseases including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia with parkinsonism linked to chromosome 17 , and in all of these diseases, NFTs are expressed in the substantia nigra (SN; Mirra et al., 1999;Poorkaj et al., 2002;Schneider et al., 2002;Wakabayashi et al., 1994). There is dramatic loss of pigmented SN neurons in PSP and FTDP-17 (Mirra et al., 1999) which may be causally related to toxic aggregation of tau. This study investigates the causal relationship of tau expression and SN dopamine neuron degeneration in an animal model. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMutation in the tau gene causes FTDP-17 (Hutton et al., 1998), and particular variants are associated with increased risk for other parkinsonian disorders, including PSP (Baker et al., 1999) and CBD (Di Maria et al., 2000). Variants may also be a risk factor for Parkinson's disease (PD;Healy et al., 2004;Martin et al., 2001). The P301L FTDP-17-related form of tau is particularly pathogenic as it exhibits accelerated filament formation in vitro (Nacharaju et al., 1999) and transgenic mice expressing P301L tau develop neurofibrillary tangles (NFTs; Lewis et al., 2000). While idiopathic PD is not associated with NFTs, tau has been demonstrated in a subpopulation of Lewy bodies (Ishizawa et al., 2003). Using a viral vector for P301L tau, we previously developed a rat model for NFT formation in the basal forebrain (Klein et al., 2004). Here we targeted wild type or P301L tau expression to the rat SN in order to study the causal relationship between neurofibrillary pathology and loss of dopamine neurons, as a number of tau...

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Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein

Cited by 1,225 publications

References 21 publications

Free radical-mediated damage to brain in Alzheimer's disease and its transgenic mouse models

Free radical-mediated damage to brain in Alzheimer's disease and its transgenic mouse models

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Tau gene transfer, but not alpha-synuclein, induces both progressive dopamine neuron degeneration and rotational behavior in the rat

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