Semenova MM, Mäki-Hokkonen AM, Cao J, Komarovski V, Forsberg KM, Koistinaho M, Coffey ET, Courtney MJ.
Rho mediates calcium-dependent activation of p38alpha and subsequent excitotoxic cell death.
Nat Neurosci. 2007 Apr;10(4):436-43.
PubMed.
Semenova et al. claim that a "necessary and sufficient" death program was activated by just a few seconds in 30 mM KCl. But when the trail of references is traced backwards to find their culture conditions, it seems that the cerebellar granule cells they used were routinely cultured in 25 mM KCl. Can a 5 mM elevation of KCl for just a few seconds really kill cerebellar granule cells? These authors and others have shown previously that high KCl is necessary for cerebellar granule cell survival. Other reports indicate that glutamate itself is a survival factor for these cells.
It would also have been nice to see citation of Bossy-Wetzel et al. (2004). These authors showed evidence for a different mechanism to activate p38 by NMDA receptors—one that could explain a caspase-independent programmed cell death that is sensitive to Bcl-2.
References:
Bossy-Wetzel E, Talantova MV, Lee WD, Schölzke MN, Harrop A, Mathews E, Götz T, Han J, Ellisman MH, Perkins GA, Lipton SA.
Crosstalk between nitric oxide and zinc pathways to neuronal cell death involving mitochondrial dysfunction and p38-activated K+ channels.
Neuron. 2004 Feb 5;41(3):351-65.
PubMed.
Many an Alzheimer’s researcher has pondered the question of whether there is some way for a neuron to release excess Aβ as a sign of ill health and imminent death. Andrea LeBlanc among others provided evidence many years ago that cultured neurons undergoing apoptosis released excess Aβ. Giuseppina Tesco and Rudy Tanzi followed up on this in 2003 in JBC and again in the Hot Topics session at ICAD in Madrid (Madrid BACE News Roundup: Part 3). There, Tesco and Tanzi reported progress in elucidating a molecular basis for apoptosis-induced Aβ generation in their demonstration that the sorting protein GGA3 was cleaved during apoptosis, thereby elevating BACE levels and/or access to APP, and so favoring Aβ generation. So, apoptosis clearly fulfills the criteria for being an amyloidogenic cell death pathway.
New data from Semenova and colleagues converge with data from our own lab and that of Giulio Pasinetti to implicate Rho signaling as another way to cause release of excess Aβ. The Semenova paper focuses on excitotoxic cell death, a death pathway long associated with excess calcium influx and excess activation of stress-associated protein kinases (SAPKs) such as p38a. Through a series of elegant and convincing experiments, Semenova demonstrates that Rho is required for glutamate-induced activation of SAPKs, and that Rho is activated when calcium levels rise. Rho toxicity was reversed by Bcl-2 and appeared to be an essential component of excitotoxic cell killing. Curiously, Rho actions were not blocked by Y-27632, prompting the conclusion that Rho was acting independently of Rho kinase (ROCK). This last conclusion should be drawn cautiously, however, since we found examples of ROCK involvement that were resistant to Y-27632. In our hands, ROCK activation is “bad” because ROCK tonically suppressed basal α-secretase-type, non-amyloidogenic APP ectodomain shedding.
In parallel work, Pasinetti and colleagues discovered that caloric restriction (CR) lowered brain amyloid burden in plaque-forming transgenic mice in a pathway that appeared to involve sirtuins. Their report coincided exactly with our report that isoprenoids modulate non-amyloidogenic α-secretase-type ectodomain shedding via ROCK. Recognizing a possible link, Pasinetti and colleagues worked in collaboration with our group to implicate ROCK as a modulator of APP metabolism downstream of CR. The linkage appears to be due to sirtuin control of ROCK expression.
In both situations, Rho is the common link that associates Aβ metabolism to CNS insults in parallel or in sequences of events that extend beyond the traditional “amyloid hypothesis” in which all neurotoxicity is caused by Aβ. Rather, it would appear that while Aβ is frequently at “the scene of the crime,” causing neurotoxicity, there are circumstances in which more indirect and complex relationships underlie its involvement.
References:
LeBlanc A.
Increased production of 4 kDa amyloid beta peptide in serum deprived human primary neuron cultures: possible involvement of apoptosis.
J Neurosci. 1995 Dec;15(12):7837-46.
PubMed.
Tesco G, Koh YH, Tanzi RE.
Caspase activation increases beta-amyloid generation independently of caspase cleavage of the beta-amyloid precursor protein (APP).
J Biol Chem. 2003 Nov 14;278(46):46074-80.
PubMed.
Pedrini S, Carter TL, Prendergast G, Petanceska S, Ehrlich ME, Gandy S.
Modulation of statin-activated shedding of Alzheimer APP ectodomain by ROCK.
PLoS Med. 2005 Jan;2(1):e18.
PubMed.
Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, Zhao W, Thiyagarajan M, MacGrogan D, Rodgers JT, Puigserver P, Sadoshima J, Deng H, Pedrini S, Gandy S, Sauve AA, Pasinetti GM.
Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction.
J Biol Chem. 2006 Aug 4;281(31):21745-54.
PubMed.
Comments
Emory U.
Semenova et al. claim that a "necessary and sufficient" death program was activated by just a few seconds in 30 mM KCl. But when the trail of references is traced backwards to find their culture conditions, it seems that the cerebellar granule cells they used were routinely cultured in 25 mM KCl. Can a 5 mM elevation of KCl for just a few seconds really kill cerebellar granule cells? These authors and others have shown previously that high KCl is necessary for cerebellar granule cell survival. Other reports indicate that glutamate itself is a survival factor for these cells.
It would also have been nice to see citation of Bossy-Wetzel et al. (2004). These authors showed evidence for a different mechanism to activate p38 by NMDA receptors—one that could explain a caspase-independent programmed cell death that is sensitive to Bcl-2.
References:
Bossy-Wetzel E, Talantova MV, Lee WD, Schölzke MN, Harrop A, Mathews E, Götz T, Han J, Ellisman MH, Perkins GA, Lipton SA. Crosstalk between nitric oxide and zinc pathways to neuronal cell death involving mitochondrial dysfunction and p38-activated K+ channels. Neuron. 2004 Feb 5;41(3):351-65. PubMed.
View all comments by Bo HuIcahn School of Medicine at Mount Sinai
Many an Alzheimer’s researcher has pondered the question of whether there is some way for a neuron to release excess Aβ as a sign of ill health and imminent death. Andrea LeBlanc among others provided evidence many years ago that cultured neurons undergoing apoptosis released excess Aβ. Giuseppina Tesco and Rudy Tanzi followed up on this in 2003 in JBC and again in the Hot Topics session at ICAD in Madrid (Madrid BACE News Roundup: Part 3). There, Tesco and Tanzi reported progress in elucidating a molecular basis for apoptosis-induced Aβ generation in their demonstration that the sorting protein GGA3 was cleaved during apoptosis, thereby elevating BACE levels and/or access to APP, and so favoring Aβ generation. So, apoptosis clearly fulfills the criteria for being an amyloidogenic cell death pathway.
New data from Semenova and colleagues converge with data from our own lab and that of Giulio Pasinetti to implicate Rho signaling as another way to cause release of excess Aβ. The Semenova paper focuses on excitotoxic cell death, a death pathway long associated with excess calcium influx and excess activation of stress-associated protein kinases (SAPKs) such as p38a. Through a series of elegant and convincing experiments, Semenova demonstrates that Rho is required for glutamate-induced activation of SAPKs, and that Rho is activated when calcium levels rise. Rho toxicity was reversed by Bcl-2 and appeared to be an essential component of excitotoxic cell killing. Curiously, Rho actions were not blocked by Y-27632, prompting the conclusion that Rho was acting independently of Rho kinase (ROCK). This last conclusion should be drawn cautiously, however, since we found examples of ROCK involvement that were resistant to Y-27632. In our hands, ROCK activation is “bad” because ROCK tonically suppressed basal α-secretase-type, non-amyloidogenic APP ectodomain shedding.
In parallel work, Pasinetti and colleagues discovered that caloric restriction (CR) lowered brain amyloid burden in plaque-forming transgenic mice in a pathway that appeared to involve sirtuins. Their report coincided exactly with our report that isoprenoids modulate non-amyloidogenic α-secretase-type ectodomain shedding via ROCK. Recognizing a possible link, Pasinetti and colleagues worked in collaboration with our group to implicate ROCK as a modulator of APP metabolism downstream of CR. The linkage appears to be due to sirtuin control of ROCK expression.
In both situations, Rho is the common link that associates Aβ metabolism to CNS insults in parallel or in sequences of events that extend beyond the traditional “amyloid hypothesis” in which all neurotoxicity is caused by Aβ. Rather, it would appear that while Aβ is frequently at “the scene of the crime,” causing neurotoxicity, there are circumstances in which more indirect and complex relationships underlie its involvement.
References:
LeBlanc A. Increased production of 4 kDa amyloid beta peptide in serum deprived human primary neuron cultures: possible involvement of apoptosis. J Neurosci. 1995 Dec;15(12):7837-46. PubMed.
Tesco G, Koh YH, Tanzi RE. Caspase activation increases beta-amyloid generation independently of caspase cleavage of the beta-amyloid precursor protein (APP). J Biol Chem. 2003 Nov 14;278(46):46074-80. PubMed.
Pedrini S, Carter TL, Prendergast G, Petanceska S, Ehrlich ME, Gandy S. Modulation of statin-activated shedding of Alzheimer APP ectodomain by ROCK. PLoS Med. 2005 Jan;2(1):e18. PubMed.
Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, Zhao W, Thiyagarajan M, MacGrogan D, Rodgers JT, Puigserver P, Sadoshima J, Deng H, Pedrini S, Gandy S, Sauve AA, Pasinetti GM. Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem. 2006 Aug 4;281(31):21745-54. PubMed.
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