Role of N-terminal tau domain integrity on the survival of cerebellar granule neurons

Amadoro, Giuseppina; Serafino, Annalucia; Barbato, Christian; Ciotti, Maria Teresa; Sacco, Alessandra; Calissano, Pietro; Canu, Nadia

doi:10.1038/sj.cdd.4401314

Cited by 66 publications

(63 citation statements)

References 64 publications

(65 reference statements)

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“…In our previous study, we observed that moderate overexpression of full-length htau in cerebellar granule cells (CGCs), although protective against K ϩ deprivation-induced cell death, caused a rapid Ϸ20% cell death, and we surmised that it would be attributed to the high level of tau expression reached in some neurons (18). To test our hypothesis we infected CGCs at 4 days in vitro with various multiplicities of infection (MOIs) of tau-(1-441) vector and Lac-Z vector as control and assayed for neuronal death 24 and 48 h later.…”

Section: Resultsmentioning

confidence: 99%

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NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation

Amadoro

Ciotti

Costanzi

et al. 2006

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

222

156

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The altered function and͞or structure of tau protein is postulated to cause cell death in tauopathies and Alzheimer's disease. However, the mechanisms by which tau induces neuronal death remain unclear. Here we show that overexpression of human tau and of some of its N-terminal fragments in primary neuronal cultures leads to an N-methyl-D-aspartate receptor (NMDAR)-mediated and caspase-independent cell death. Death signaling likely originates from stimulation of extrasynaptic NR2B-subunit-containing NMDARs because it is accompanied by dephosphorylation of cAMP-response-element-binding protein (CREB) and it is inhibited by ifenprodil. Interestingly, activation of NMDAR leads to a crucial, sustained, and delayed phosphorylation of extracellular-regulated kinases 1 and 2, whose inhibition largely prevents tau-induced neuronal death. Moreover, NMDAR involvement causes the fatal activation of calpain, which, in turn, degrades tau protein into a 17-kDa peptide and possibly other highly toxic N-terminal peptides. Some of these peptides are hypothesized, on the basis of our in vitro experiments, to initiate a negative loop, ultimately leading to cell death. Thus, inhibition of calpain largely prevents tau degradation and cell death. Our findings unravel a cellular mechanism linking tau toxicity to NMDAR activation and might be relevant to Alzheimer's disease and tauopathies where NMDARmediated toxicity is postulated to play a pivotal role. extracellular-regulated kinase ͉ mitogen-activated protein kinase ͉ neurodegenerative diseases ͉ glutamate receptors ͉ Alzheimer's disease

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Section: Resultsmentioning

confidence: 99%

“…Viable CGCs and cortical neurons were quantified by the MTT tetrazolium salt assay, by counting the number of intact nuclei (18), or by counting the number of condensed nuclei after Hoechst 33342 staining.…”

Section: Infection Of Neuronsmentioning

confidence: 99%

NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation

Amadoro

Ciotti

Costanzi

et al. 2006

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

222

156

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“…However, it is very difficult to show that such a mechanism can (and more importantly [108,109,138,139,213,214].…”

Section: Is Tau a Prion?mentioning

confidence: 99%

Untangling the role of tau in Alzheimer’s disease: A unifying hypothesis

Bhatia

Hall

2013

Translational Neuroscience

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Recent investigations into the etiology and pathogenesis of Alzheimer's disease (AD) in the past few years have expanded to include previously unexplored and/or disconnected aspects of AD and related conditions at both the cellular and systemic levels of organization. These include how AD-associated abnormalities affect the cell cycle and neuronal differentiation state and how they recruit signal transduction, membrane trafficking and protein transcytosis mechanisms to produce a neurotoxic syndrome capable of spreading itself throughout the brain. The recent expansion of AD research into intercellular and new aspects of cellular degenerative mechanisms is causing a systemic re-evaluation of AD pathogenesis, including the roles played by well-studied elements, such as the generation of Aβ and tau protein aggregates. It is also changing our view of neurodegenerative diseases as a whole. Here we propose a conceptual framework to account for some of the emerging aspects of the role of tau in AD pathogenesis.

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“…34 Furthermore, if one of such truncated tau forms was introduced into the same healthy neurons by adenovirusmediated transduction, it evoked a massive and rapid cell death 35 involving extrasynaptic NR2B-subunit-containing NMDARs, dephosphorylation of cAMP-response-elementbinding protein, sustained and delayed activation of extracellular-regulated kinases 1/2 and calpain-I. 36 In addition, the pro-apoptotic shifting to a low potassium medium induced a marked failure of mitochondrial oxidative phosphorylation, accompanied by a dramatic intracellular ATP drop and by an increased production of reactive oxidative species.…”

Section: Amyloidogenesis and Apoptosismentioning

confidence: 99%