Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice

Dineley, Kelly T.; Hogan, Dale; Zhang, Wen Ru; Taglialatela, Giulio

doi:10.1016/j.nlm.2007.03.010

Cited by 133 publications

(146 citation statements)

References 39 publications

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“…The involvement of CaN in the neurodegenerative process and memory impairment in AD and PRE remains a controversial issue (Wang et al, 1999;Norris et al, 2005;Biasini et al, 2006;Dineley et al, 2007). In a previous study we demonstrated that Ab and PrP peptides trigger a caspase-3-dependent apoptotic neuronal death pathway, involving CaN and cyt c release from mitochondria (Agostinho and Oliveira, 2003).…”

Section: Discussionmentioning

confidence: 96%

“…1). Accordingly it was reported that FK506 reduces the activity of this phosphatase in several brain regions of an AD mice model, improving the cognitive deficits observed in these animals (Dineley et al, 2007).…”

Section: Discussionmentioning

confidence: 97%

“…However, the manner by which Ab and PrP peptides affect CaN remains controversial. A recent study showed that CaN activity was augmented in cortex, hippocampus and cerebellum of transgenic AD animal models, and the accumulation of Ab was coincident with CaN upregulation (Dineley et al, 2007). Moreover, it was demonstrated that Ab peptides can induce CaN activation, via Ca 2+ influx through a7 nicotinic acetylcholine receptors, in cortical neurons (Snyder et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

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Overactivation of calcineurin induced by amyloid-beta and prion proteins

Agostinho

Lopes

Velez

et al. 2008

Neurochemistry International

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Amyloid-beta protein (Ab) and the scrapie isoform of prion protein (PrP Ss ) have a central role in the pathogenesis of Alzheimer's disease (AD) and prion-related encephalopathies (PRE), respectively. In both disorders, the deposition of these misfolded proteins is accompanied by apoptotic neuronal loss. However, the pathogenesis and molecular basis of Ab-and PrP Sc -neurotoxic effects are not completely understood. The Ca 2+ / calmodulin-dependent phosphatase calcineurin (CaN), through the dephosphorylation of the proapoptotic protein BAD, may be the link between Ca 2+ homeostasis deregulation and apoptotic neuronal death. In this study we used primary cultures of rat brain cortical neurons in order to investigate whether Ab and PrP affect CaN activity. We observed that synthetic peptides of Ab (Ab 25-35 and Ab 1-40 ) and PrP (PrP 106-126 ) increased CaN activity, but did not affect the levels of this protein phosphatase. Moreover, we found that these peptides reduced the levels of BAD phosphorylated at serine residue 112, and this effect was prevented by the CaN inhibitor FK506. Since dephosphorylated BAD translocates to mitochondria, where it triggers cytochrome c release, we determined the levels of BAD in mitochondrial and cytosolic fractions. The data obtained showed that Ab-and PrP-treated neurons had higher levels of BAD in mitochondria than control neurons. This increase in mitochondrial BAD levels was matched by a decrease in cytochrome c. FK506 prevented the alterations of mitochondrial BAD and cytochrome c levels induced by Ab and PrP peptides. Taken together the data suggest that Ab and PrP increased CaN activity, inducing BAD dephosphorylation and translocation to mitochondria and, subsequently, cytochrome c release that may trigger an apoptotic cascade. Therefore, therapeutic strategies targeting CaN might be valuable for these neurodegenerative disorders. #

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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Overactivation of calcineurin induced by amyloid-beta and prion proteins

Agostinho

Lopes

Velez

et al. 2008

Neurochemistry International

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“…The level of CaN was found to be elevated in aged rats and in an APP transgenic mouse model of AD that display defects in cognition. 68,69 In the case of the transgenic mouse, the defects in cognition could be reversed by FK506, which is an inhibitor of CaN (Fig. 4).…”

Section: Alzheimer Diseasementioning

confidence: 97%

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

Berridge

2013

Prion

181

129

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“…of the phosphorylated CREB was reduced and it was restored by treatment with FK506 (32). In the nuclear fraction of AD brains, a cleaved fragment of CaN (cCaN) is increased and the cleavage activates the phosphatase (33).…”

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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.

143

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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Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice

Cited by 133 publications

References 39 publications

Overactivation of calcineurin induced by amyloid-beta and prion proteins

Overactivation of calcineurin induced by amyloid-beta and prion proteins

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

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

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