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.
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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.
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