Age-Dependent Impairment of Cognitive and Synaptic Function in the htau Mouse Model of Tau Pathology

Polydoro, Manuela; Acker, Christopher M.; Duff, Karen; Castillo, Pablo E.; Davies, Peter

doi:10.1523/jneurosci.1065-09.2009

Cited by 298 publications

(309 citation statements)

References 37 publications

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“…The hTau mice express human genomic wild-type Tau on a mouse Tau KO/C57Bl/6J background and begin to develop Tau pathology at 2 months of age, which begins to plateau around 15-16 months of age (21,22). Synaptic and cognitive deficits and NFTs are present at 11-12 months of age, and neuron loss is seen by 17 months of age.…”

Section: Methodsmentioning

confidence: 99%

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Curcumin Suppresses Soluble Tau Dimers and Corrects Molecular Chaperone, Synaptic, and Behavioral Deficits in Aged Human Tau Transgenic Mice

Zuo

Yang

et al. 2013

Journal of Biological Chemistry

177

164

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Background: Various types of Tau aggregates in AD brains may differentially impact neurodegeneration. Results: Curcumin selectively suppresses soluble Tau dimers and corrects molecular chaperone, synaptic, and behavioral deficits. Conclusion: A drug increasing HSPs involved in Tau clearance reduced Tau dimers and improved cognition. Significance: Curcumin that reduced Tau dimers and increased molecular chaperones was efficacious without altering insoluble Tau.

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Section: Methodsmentioning

confidence: 99%

“…Because AD lacks Tau mutations, we chose wild-type human Tau (hTau) transgenic mice that exhibit NFTs, neuron loss, and cognitive deficits by 12 months of age (21,22). We first evaluated the association of different p-Tau species with cognitive and synaptic deficits.…”

mentioning

confidence: 99%

Curcumin Suppresses Soluble Tau Dimers and Corrects Molecular Chaperone, Synaptic, and Behavioral Deficits in Aged Human Tau Transgenic Mice

Zuo

Yang

et al. 2013

Journal of Biological Chemistry

177

164

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“…Earlier investigations into AD-related synaptic damages have been mainly focused on the toxic effects of Aβ (11). Recently, an emerging role of tau in synaptic impairment has been shown (12). For instance, overexpression of human mutant tau in mice induces synaptic degeneration even in the absence of tangles (13,14) and reducing endogenous tau in mouse models carrying the mutated amyloid precursor protein (APP) prevents the cognitive deficits and synaptic loss (15).…”

mentioning

confidence: 99%

Tau accumulation induces synaptic impairment and memory deficit by calcineurin-mediated inactivation of nuclear CaMKIV/CREB signaling

Yin

Gao

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

146

119

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Intracellular accumulation of wild-type tau is a hallmark of sporadic Alzheimer's disease (AD), but the molecular mechanisms underlying tau-induced synapse impairment and memory deficit are poorly understood. Here we found that overexpression of human wild-type full-length tau (termed hTau) induced memory deficits with impairments of synaptic plasticity. Both in vivo and in vitro data demonstrated that hTau accumulation caused remarkable dephosphorylation of cAMP response element binding protein (CREB) in the nuclear fraction. Simultaneously, the calcium-dependent protein phosphatase calcineurin (CaN) was up-regulated, whereas the calcium/ calmodulin-dependent protein kinase IV (CaMKIV) was suppressed. Further studies revealed that CaN activation could dephosphorylate CREB and CaMKIV, and the effect of CaN on CREB dephosphorylation was independent of CaMKIV inhibition. Finally, inhibition of CaN attenuated the hTau-induced CREB dephosphorylation with improved synapse and memory functions. Together, these data indicate that the hTau accumulation impairs synapse and memory by CaN-mediated suppression of nuclear CaMKIV/CREB signaling. Our findings not only reveal new mechanisms underlying the hTau-induced synaptic toxicity, but also provide potential targets for rescuing tauopathies.is the most common neurodegenerative disorder characterized clinically by progressive memory loss (1). The extracellular precipitation of β-amyloid (Aβ) (2), intracellular tau accumulation forming neurofibrillary tangles (3), and profound synapse degeneration are hallmark pathologies in AD brains (4, 5). Studies show that formation of neurofibrillary tangles is positively correlated with the degree of dementia symptoms (6), and the Aβ toxicity needs the presence of tau (7). These data suggest a crucial role of tau accumulation in neurodegeneration and the cognitive impairments in patients with AD. As a cytoskeleton protein, how tau accumulation causes memory deficits is not fully understood.Synapse is the fundamental unit for learning and memory. Dysfunction of synaptic connections is recognized as the cause of memory impairments, and significant synapse loss has been observed in mild cognitive impairment (MCI) and in earlier stages of AD (8). In AD mouse models, synapse impairments appear before the onset of memory deficit (9), whereas amelioration of synapse loss by administration of estradiol preserves cognitive functions (10). Earlier investigations into AD-related synaptic damages have been mainly focused on the toxic effects of Aβ (11). Recently, an emerging role of tau in synaptic impairment has been shown (12). For instance, overexpression of human mutant tau in mice induces synaptic degeneration even in the absence of tangles (13, 14) and reducing endogenous tau in mouse models carrying the mutated amyloid precursor protein (APP) prevents the cognitive deficits and synaptic loss (15).Among many structural or functional proteins involved in synapse development and memory formation, cAMP response element binding protein (CREB) is...

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“…These observations imply that preventing δTau formation could cause behavioral, synaptic and biochemical alterations approximating those observed in some animal models of tauopathy. [45][46][47][48] Therefore, cleavage of Tau at D 421 could represent a mechanism aimed to prevent hyper-phosphorylation and precipitation of Tau.…”

Section: Discussionmentioning

confidence: 99%

Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations

et al. 2017

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TAU mutations are genetically linked to fronto-temporal dementia (FTD) and hyper-phosphorylated aggregates of Tau form neurofibrillary tangles (NFTs) that constitute a pathological hallmark of Alzheimer disease (AD) and FTD. These observations indicate that Tau has a pivotal role in the pathogenesis of neurodegenerative disorders. Tau is cleaved by caspases at Aspartate 421 , to form a Tau metabolite known as δTau; δTau is increased in AD, due to the hyper-activation of caspases in AD brains. δTau is considered a critical toxic moiety underlying neurodegeneration, which initiates and facilitates NFT formation. As Tau is a therapeutic target in neurodegeneration, it is important to rigorously determine whether δTau is a toxic Tau species that should be pharmacologically attacked. To directly address these questions, we have generated a knock-in (KI) mouse called Tau DN -that expresses a Tau mutant that cannot be cleaved by caspases. Tau DN mice present short-term memory deficits and synaptic plasticity defects. Moreover, mice carrying two mutant Tau alleles show increased total insoluble hyper-phosphorylated Tau in the forebrain. These data are in contrast with the concept that δTau is a critical toxic moiety underlying neurodegeneration, and suggest that cleavage of Tau by caspases represents a negative feedback mechanism aimed to eliminate toxic Tau species. Alternatively, it is possible that either a reduction or an increase in δTau leads to synaptic dysfunction, memory impairments and Tau pathology. Both possibilities will have to be considered when targeting caspase cleavage of Tau in AD therapy.

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Age-Dependent Impairment of Cognitive and Synaptic Function in the htau Mouse Model of Tau Pathology

Cited by 298 publications

References 37 publications

Curcumin Suppresses Soluble Tau Dimers and Corrects Molecular Chaperone, Synaptic, and Behavioral Deficits in Aged Human Tau Transgenic Mice

Curcumin Suppresses Soluble Tau Dimers and Corrects Molecular Chaperone, Synaptic, and Behavioral Deficits in Aged Human Tau Transgenic Mice

Tau accumulation induces synaptic impairment and memory deficit by calcineurin-mediated inactivation of nuclear CaMKIV/CREB signaling

Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations

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