Panelists: Paul Coleman, Carl Cotman, Mark Smith, George Perry, Mark Mattson (in absentia)

Audience: Luc Buee, Brian Cummings, Donna McPhie, June Kinoshita, Ben Wolozin, Melissa, and a mysterious Dr. Jekyll from the other side of the planet.

View the panelists' responses to some preliminary questions.
Submit a question or comment to the panelists.

This transcript has been edited to make the discussion more coherent and to protect the innocent.

Paulcoleman says, "June, is Boston time noon yet?"

Junekinoshita says, "Welcome all. Let's wait a few minutes for stragglers."

Mcphie enters.

Smith says, "Where's Mattson?"

Junekinoshita says, "Hi Donna (or is that Rachael Neve in disguise?)"

Junekinoshita says, "I'm filling in for Mark, whose system keeps crashing on iChat."

Mcphie says, "Hi June!"

Junekinoshita says, "Mattson sent me prepared remarks by e-mail. If you have questions for him, I can transmit them by e-mail to Mark during this discussion."

Cummings says, "George has a statement prepared. He cannot answer until he unleashes his prepared statement."

Smith says, "Tell Mark to use the Java Client not i-Chat when he logs selection...we crashed too."

Junekinoshita says, "I think we can begin."

Cummings says, "Yes, ichat is a memory hog. If you ar going to use it, you must allocate more memory to browser or crash."

Smith says, "Tick tock tick tock."

Carlcotman says, "How would you like to start?"

Junekinoshita says, "Paul Coleman will be moderating."

Paulcoleman says, "So let's start with the statement George wanted to make and take it from there."

Cummings says, "I'll start with coffee and a doughnut."

Perry says, "Opening Statement from George Perry and Mark A. Smith: We think it is important to emphasize that this topic may not now be as controversial as one might expect or as it was even a few months ago. In fact, there appears to be a consensus that while much of the apoptotic machinery is present, it may not necessarily be engaged in promoting cell death. Is this apoptosis, avoidance of apoptosis or another phenomena? That is the important question, i.e., what do we call this? Smith favors "abortosis", i.e., abortive apoptosis, while Perry favors "avoidosis", i.e., avoidance of apoptosis. Whatever this shift, it is away from finality, and there is no need to send sympathy cards to the neurons. More appropriate may be "Best Wishes for a Happy Recovery!" The major question is how do cells manage to survive at all in AD in the face of deleterious changes occurring within neurons?"

Cummings nods solemnly.

{PRIVATE} Cummings tells Carlcotman "Sounds like they are trying to steal your fire."

Paulcoleman says, "George's statement is interesting. But it is clear that some of the genes usually associated with apoptosis are involved in AD. The term apoptosis carries much baggage, but what counts is the cascade of expression"

Smith says, "Yes, but solely with AD"

Carlcotman says, "We agree that in large part what neurons may be doing is preventing terminal apoptosis. However, it would probably be more structured to address some of the original issues on the table."

Paulcoleman says, "Go ahead Carl"

Perry says, "Do you mean the questions [that were sent around in advance]?"

Carlcotman says, "Well, Re: the first question regarding what the most compelling evidence for apoptosis in AD is. We feel that the most compelling issue is 1) the presence of morphologically apoptotic nuclei; 2) the absence of a large degree of necrosis; 3) the fact that neuronal loss exceeds NFT formation in at least some areas; and 4) the fact that apoptotic mechanisms appear to affect synapses and neurites."

Smith says, "Regarding point 1. This is seldom ever seen ...true?"

Perry says, "1) There are very few apoptotic nuclei in AD and 3) NFT may be a protective response"

Junekinoshita says, "Here are Mark's comments regarding the evidence for apoptosis. I think it's useful for people to see them. "

Junekinoshita says, "Mark makes 4 points: 1) "patchy" distribution of degenerating neurons within affected brain regions."

Paulcoleman says, "Can we agree that PCD [programmed cell death] can be used here to avoid the baggage of apoptosis?"

Lucbuee enters.

Smith says, "Makes no difference to me."

Perry says, "I am not sure that these terms are equivalent. Predominantly because apoptosis does have baggage."

Carlcotman says, "No, PCD and apoptosis cannot be equated."

Paulcoleman says, "The intent was not to equate them, but to adopt a more general term"

Carlcotman says, "PCD is not a more general term."

Cummings says, "Does this avoid the problem? Are Perry and Smith saying that the neuronal loss in AD is not due to apoptosis or PCD, or that only some of it is?"

Smith says, "Cells do not predominantly die by apoptosis"

Carlcotman says, "Then how do we account for up to 90% neuronal loss?"

Smith says, "Cell death!"

Paulcoleman says, "The proposal of NFT as protective has analogy to the inclusions in HD, which some now think are protective"

Smith says, "How this occurs is unlikely through apoptosis, or at least apoptosis as defined."

Carlcotman says, "How do you define apoptosis?"

Smith says, "Perry is answering."

Perry says, "Apoptosis is a series of changes that in neurons involves mitochondrial disruption in nuclear condensation and eventually phagocytosis of the remaining cell body by macrophages. This is seldom seen in AD."

Carlcotman says, "Yes, it's seldom seen because few neurons are in active apoptosis at any give time, this is consistent with the progression of cell loss in the disease."

Perry says, "Obviously, cells do die in AD. But it takes time."

Junekinoshita says, "Can I submit Mark's response to Perry's point?"

Smith says, "Yes"

Carlcotman says, "We have suggested that neurons as nondividing cells have a series of apoptotic checkpoints that compensate for neuronal injury and prolong entry into terminal apoptosis. Therefore, while few actively apoptotic neuronas are present, many TUNEL positive neurons can be present."

Carlcotman says, "In support of this negative regulatory factors are expressed in injured neurons in AD (e.g., bcl-2, gad45, p16)."

Junekinoshita says, "Mattson says: That AD is a slow, chronic neurodegenerative process strongly favors apoptotic (vs. necrotic) mode of neuronal death. Numerous studies (in cell culture and in vivo) have shown that lower intensity, longer duration insults will induce neuronal apoptosis, whereas higher intensity insults will induce necrosis" (more to come)."

Junekinoshita says, "[Continuing to transmit Mattson's comments] "Examples include titration of exposure to glutamate, iron and A beta in culture, and the gradient of neuonal injury in focal ischemia - necrosis in the ischemic core and apoptosis in the penumbra."

Perry says, "Yes June. But, is ten years the usual time course for culture studies? When one is talking about long term changes the time frame is usually days in culture. Instead in AD, only a few neurons are ever actually dying over any time frame. Therefore, what is in fact changing is something that takes years to develop or instead is a process that is avoided -- avoidosis."

Smith says, "But [getting back to Carl's point,] TUNEL is late. Are [the neurons] capable of stopping [apoptosis] at this point?"

Perry says, "TUNEL positivity is not specific for the nuclear changes of apoptosis."

Smith says, "Response to Carl......as with other things, the question is whether these are specific for apoptosis."

Carlcotman says, "Apoptotic bodies, caspase activation, the appearance of caspase-dependent cleavage products are all clearly apoptotic changes."

Jjohnso2 enters.

Smith says, "Yes, but these are the rarely seen events...the other events are widespread and usually equated to apoptosis."

Mattson enters.

Carlcotman says, "What other events?"

Mattson leaves [system crash?]

Smith says, "bcl, bax etc"

Carlcotman says, "We don't equate bcl-2 with terminal apoptosis, we say that these pathways regulate apoptosis and may delay death commitment."

Smith says, "I know you do not, but others have. Related to this, how long would you expect a TUNEL positive cell to survive in vivo?"

Perry says, "Regarding apoptosis or other forms of cell death in culture: there are ample suggestions that this is very situation-dependent and predominantly influenced by the artifacts intrinsic to cells maintained outside of their natural environment."

Paulcoleman says, "In addition to bcl-2 there are a number of cellular defenses mounted in AD. Why are they not operating as effectively in vitro?"

Jc6 enters.

Smith says, "Perhaps they are!"

Perry says, "But they may very well be doing so. The neurons are alive!"

Carlcotman says, "Perhaps a very long time. This is the point: There are DNA and other cellular repair mechanisms that are active as a part of an apoptotic checkpoint in AD neurons, and therefore few cells apoptose at any given time."

Smith says, "Is this apoptosis!"

Carlcotman says, "The problem may be that the cell death inducers (AGEs, oxidative stress, A beta) don't go away, and so neurons may not ever be able to completely recover and exhibit prolonged damage."

Perry says, "But they do! That's the point! These neurons are majorily damaged and they are alive. The question is how they do it."

Smith says, "Rar Rar!"

Cummings says, "Apoptotic nuclei (by morphological criteria) ARE seen in AD, even if they are rare. Thus, avoidosis isn't really accurate. If apoptosis occurred at a very slow rate, this would account for two things, (1) seeing only a few apoptotic nuclei in an AD brain sections, and (2) the large loss of neurons over a ten year period."

Smith says, "Great, then what about ABORTOSIS."

Cummings says, "Mark Smith, clarify what you mean and maybe I can comment."

Smith says, "Abortosis = abortive apoptosis...in other words perhaps initiated in large numbers of cells but then aborted in all/most."

Perry says, "Yes, the neurons that actually die may be dying by apoptosis. But all the neurons, ALL the neurons, show apoptotic markers. Therefore, apoptotic markers do not mean, and cannot mean, that the pathway classically defined as apoptosis or most concepts of programmed cell death are activated because they take at most days."

Junekinoshita says, "Well, maybe we're just ignorant about actual apoptotic processes in living human brains."

Perry says, "June, I think you may be right."

Carlcotman says, "All neurons do not show apoptotic markers."

Carlcotman says, "Why do you say that all neurons show apoptotic markers?"

Perry says, "Did you not show that all neurons show TUNEL positivity?"

Carlcotman says, "No"

Paulcoleman says, "The fact that all neurons do not show current apoptotic markers need not mean that at some time they do not go through this state."

Perry says, "Which vulnerable neurons do not show TUNEL positivity? We also performed end labeling and found that all vulnerable neurons as well as some other cells showed DNA fragmentation. There was little difference between cells of the same population. This is the same pattern seen for oxidative damage."

Smith says, "Paul...but most do show "apoptotic markers" the question is whether they mean apoptosis."

Paulcoleman says, "The fact that few cells show criteria for apoptosis suggests that they are in the state indicated by these criteria for only a short time. But what is leading up to this state?"

Junekinoshita says, "That's the key question. If cells are avoiding apoptosis, what is stressing them out in the first place?"

Carlcotman says, "Probably what leads up to the state is a series of accumulating damage/inducers in which the neuron is being driven towards apoptosis but attempting to compensate and repair the damage."

Smith says, "What causes...take your pick of your favorite inducer....ox stress or cell cycle is mine...surprising"

Junekinoshita says, "Re: stressors, are we all under increased ox stress with age and just some individuals are more vulnerable to its effects?"

Junekinoshita says, "Or is it that some or us are generating more ox radicals?"

Cummings says, "Can we agree on Mark's term abortosis, which would imply that some cells do in fact undergo apoptosis while others manage to avoid it. This sounds like a process that Cotman and Anderson have being suggesting for several years."

Smith says, "Yes, but without the funky name!"

Smith grins evilly.

Perry says, "I still like "avoidosis"."

Junekinoshita says, "Sounds like a case of terminal procrastination."

Smith says, "Perry is very 'old-school'"

Carlcotman says, "We call it an apoptosis checkpoint cascade."

Paulcoleman says, "I certainly would like to see some agreement that would avoid semantics and get to mechanisms."

Carlcotman says, "ok"

Carlcotman says, "TUNEL cannot be equated with either apoptotic or necrotic cell death."

Cummings laughs hysterically.

Perry says, "Carl, but isn't that what you published in several articles????? Can you clarify this?"

Carlcotman says, "Yes. As one example you could argue that, in parallel with the cell cycle in dividing cells, there are a series of compensatory mechanisms (bcl-2, gad45, p16...) that repair damage and prevent commitment to terminal apoptosis"

Perry says, "But Carl, back to the question of TUNEL."

Cummings says, "Carl, why are so many cells TUNEL positive? They are not all apoptotic?"

Smith says, "Go Cummings!"

Carlcotman says, "Absolutely not. Only TUNEL-positive cells with apoptotic morphologies (condensed chromatin/apoptotic bodies) are apoptotic, the rest are merely damaged. ALso TUNEL labeling is a function of disease progression. Even early on there is dramatic labeling before cell loss."

Perry says, "Is that what you said in your earlier papers?"

Carlcotman says, "Yes"

Carlcotman says, "Cummings - get back to work!"

Cummings says, "So ApopTag is a lousy name for a labeling kit !"

Carlcotman says, "YES!!!"

Cummings bows gracefully.

Perry says, "Then why did you use it? And how often are nuclear morphology of apoptosis seen in AD? And didn't Lassmann as well as Lucassen find that there was no increase in this morphology in AD?"

Carlcotman says, "Because it is an indicator of damage, isn't that of interest in AD?"

Carlcotman says, "I'm not sure what other people don't see as much morphology as we do, all I can say is that we have exceptional tissue quality. Short-postmortem, and excellent fixation."

Perry says, "But, that is not the story I remember from the earliest papers. Even to this day, I have manuscripts on my desk for review that cite your work suggesting that apoptosis involves all the neurons in AD. How did so many wise authors make this error?"

Carlcotman says, "That is never what we said in our manuscripts."

Cummings says, "George, classic example of people mis-citing others work."

Cummings says, "Anderson and Cotman argued DNA damage back in the initial papers."

Carlcotman says, "In fact, we were the first to point out that this didn't make sense (anderson j neurosci 1996)"

Paulcoleman says, "Carl, your last statement suggests you send some sections to others from your material."

Paulcoleman says, "Since you suggest that your ability to see morphology reflects short PMD and fixation, why not send some material to others to see if they replicate?"

Carlcotman says, "Absolutely we would be pleased to send sections, tissue, etc"

Smith says, "What about work with Su?"

Carlcotman says, "The Neuroreport paper?"

Smith says, "Among others."

{PRIVATE} Cummings tells Smith "Su is one of us, he wouldn't say anything we wouldn't agree with :)"

Carlcotman says, "That was the only one before the Anderson paper"

Junekinoshita says, "What I want to know is this: Are neurons going down an apoptotic pathway as a response to some nonspecific insults (i.e. ox stress, A beta toxicity, etc.), or is the apoptosis being triggered by a specific aberrant molecule?"

Smith says, "Why is A beta or ox stress non-specific....It is likely as specific as anything!"

Carlcotman says, "We would say that it's striking that almost every risk factor in AD is proapoptotic - A beta, oxidative injury, genetic mutations, excitotoxicity etc..."

Paulcoleman says, "So, in answer to June, would you suggest Carl that there are many paths to apoptotic cell death?"

Junekinoshita says, "Reminds me of an Agatha Christie mystery (Death on the Nile?) in which everyone has a motive and it turns out everyone is the murderer."

Cummings smiles at Junekinoshita.

Carlcotman says, "Paul- yes we would suggest that there are many pathways, from ic mediated to receptor mediated."

Perry says, "On the issue of the response to an insult, I think that apoptotic changes are specifically related to problems of energy metabolism involving mitochondria and necessary compensatory changes to maintain life."

{PRIVATE} Cummings tells Carlcotman "Also indicate that paraffin poses problem....and remind them of autolysis curve"

Perry says, "Maybe, Carl, we are agreeing on what's really happening in AD. The changes we and you have documented are not a path to rapid death. Can we agree on that?"

Carlcotman says, "We say yes to Perry - I think we do agree that cell death is not necessarily rapid, but reflects a struggle to compensate for injury."

Carlcotman says, "Perry's comment about responses to insult is interesting because Mark's group and ours have both argued that neuronal processes can mobilize apoptotic pathways and degenerate via a type of local apoptosis."

Smith says, "What is local apoptosis!"

Smith says, "Is that like cell-free apoptosis?"

Carlcotman says, "We have called it neuritic apoptosis. Mark calls it synapoptosis. It is defined by the activation of caspases, phosphotidylserine inversion, and presence of caspase cleavage products in neuronal processes selectively exposed to insult or in synaptosomal preps (Ivins neurobio disease 1998)"

Perry says, "Yes, I would imagine that synapses would be particularly affected since they rely totally on microtubules for maintenance. Calcium homeostasis is the major control mechanism of microtubules. The synaptophysin changes of AD may reflect a loss of synaptic vesicle transport as suggested by Terry rather than frank synapse loss."

Junekinoshita says, "Let me introduce a question that, perhaps, also addresses the issue of why neurons appear to be heading down an apoptotic pathway in AD: Are we seeing a recapitulation of a developmental process? If so, why is it happening?"

Carlcotman says, "Perhaps some neurons do in fact recapitulate developmental events, but in development, the inducers are more likely to be substrate or trophic factor deficiencies, whereas in AD the inducers are things like A beta and other insults, and may may give rise to a more complicated set of molecular pathways"

Smith says, "Why not the same as development which then, in old brain, leads to A beta and other insults? The chronology is far from clear."

Carlcotman says, "Well, there is no oxidative stress, AGEs or A beta in development."

Perry says, "I am not sure the changes of AD that appear to be related to development are really the same because in development, neurons die rapidly following entry into apoptosis and do not linger for years. In AD, these changes may instead reflect protective responses rather than a frank developmental one. But of course neurons in late age are likely to rely on mechanisms of earlier life."

Carlcotman says, "We agree with Perry."

Smith says, "Wow"

Perry says, "Are we sure there is no oxidative stress or amyloid beta earlier in life?"

Carlcotman says, "The other issue is that as Davies and others have suggested, some of the cell cycle mechanisms, which may contribute to an apoptosis checkpoint, if prolonged could lead to NFT formation."

Carlcotman says, "In Down syndrome tissue the earliest A beta is seen at about 16 years, not before. And that's with APP acceleration."

Junekinoshita says, "Allow me to post Mark's response to an earlier question re: time course: "We do not know the time course of the cell death process in individual neurons in AD. Moreover, an individual neuron may be slowly and progressively compromised in terms of its function and homeostasis for a very long period (e.g. months to year) before it initiates the apoptotic process which then leads to more rapid cell death. I agree it is likely that neurons are stressed for a long time before they die. I also agree it's likely that neurons respond to stress by activating mechanisms designed to prevent cell death. I strongly disagree that this argues against an apoptotic mechanism of neuronal death in AD. I surmise that apoptosis is the most likely mode of cell death in cells that succumb after a long battle against the forces of evil at work in the AD brain."

Perry says, "Carl, I think you as well as Peter Davies may be correct."

Smith says, "Most cells with altered cell cycle elements do not contain NFT, so this may be a reasonable speculation."

Carlcotman says, "Yea Mark."

Smith says, "Smith or Mattson?"

Carlcotman says, "Mattson. Sorry :)"

Carlcotman says, "It seems like there is some debate still on when and where cell cycle proteins are, this is probably also a factor of disease state and brain region"

Perry says, "My comments are not whether cells die by apoptosis. It is whether all the neurons that show apoptotic markers have entered an apoptotic pathway. June, we cannot underestimate the importance of this distinction. It is the difference of sending a wreath or a get well card."

Smith says, "The cell cycle stuff certainly needs further work..it's interesting."

Carlcotman says, "We agree, this is the most important issue. However, again, all neurons with TUNEL labeling have not entered an apoptotic pathway."

Smith says, "TUNEL IS AN END EVENT SURELY."

Carlcotman says, "We were commenting on the extended Mattson response, however, we think we also have some agreement with Smith and perry"

Perry says, "But most studies on apoptosis suggest DNA fragmentation is one of the last events. Of course, this would not be the case if fragmentation was the result of oxidative events only."

Carlcotman says, "ABsolutely not - TUNEL does not equal double strand breaks. Terminal transferase can also label single strand breaks/nicks and even transcribing cells or cells in DNA repair"

Smith says, "ie., oxidative strand breaks."

Carlcotman says, "Yes."

Perry says, "Okay. I agree."

Smith says, "So, without TUNEL where is the apoptosis story?"

Carlcotman says, "Again, it's the MORPHOLOGY."

Smith says, "But what morphology...I know you see it but others do not...therefore rare rare rare."

Carlcotman says, "Of course, there is also a growing literature on the caspase story in AD (e.g. Greg Cole's work)"

Smith says, "We also have great caspase data but do not equate to apoptosis."

Perry says, "But Carl, how many papers have documented substantial nuclear and other specific changes of apoptosis in a substantial number of neurons in AD?"

Smith says, "He's tough."

Cummings says, "Yea, he's tough, but I think we are turning him."

Cummings listens to Smith.

Smith says, "He'll be back."

Carlcotman says, "In fact, we agree that the number of actively apoptotic events in the AD brain should be very small. You have estimated that this would equate to about 1/4000 neurons with active apoptosis. In fact, based on the number of neurons in 50 micron sections of STS, Perry and Smiths predictions of the number of apoptotic cells would translate to roughly 25 actively (morphologically) apoptotic neurons per 50 micron section - and this is about what we see at any given time in any given section."

Perry says, "Has that figure been confirmed by other laboratories?"

Carlcotman says, "Many from our group, Athena neurosciences have also seen it, and at Case Western."

Smith says, "Who at CWRU?"

Carlcotman says, "Don't think it's been published. We are looking for the Case Reference - Herrup?"

Carlcotman says, "We think the real point here is that there is a need for much more precise quantification based on disease progression and brain area."

Smith says, "Herrup did some confirmatory work on cell cycle...not on apoptosis..if its the J. Neurosci paper."

Smith says, "Q? Do we think this is therapeutically relevant?"

Carlcotman says, "Also - the Stadelmann paper (J Neuropath?) comments on apoptotic morphologies in AD in a few cells."

Perry says, "Or is the point the need for a precise definition of what is being studied?"

Cummings says, "Therapeutically relevant to block apoptosis, probably not, but to help with DNA repair, maybe yes."

Carlcotman says, "Yes we think its therapeutically relevant. The vast majority of neuronal loss in AD occurs in the absence of NFT formation (Gomez-Isla and Hyman) and in the absence of necrotic morphology. Therefore, taken with the neuritic apoptosis issue, this is clearly an important target for early intervention."

Smith says, "Agree, with DNA comment, because cause irrelevant, only target."

Cummings says, "Carl, what target, blocking apoptosis or aiding in cell stabilization, DNA repair?"

Perry says, "Yes, and note Lassmann (Stadelmann first author) agreed with the conclusions of our recent letter in Science and was an author of that letter."

Carlcotman says, "Debating the Lassman paper involves far more subtle issues than we can get into here and stay on target."

Carlcotman says, "It's clear that apoptosis reflects a series of thresholds to injury. The goal would be to raise the threshold for apoptosis and allow the cell to recover."

Perry says, "Most neurons that die in AD do not have NFT. We also found reported this several years ago before Hyman."

Carlcotman says, "We agree."

Perry says, "Further, in recent studies, we found that oxidative damage was reduced between 50-60% by the presence of an NFT in a neuron."

Carlcotman says, "We don't argue that NFTs could be protective against some types of insult, however, these neurons are clearly not healthy and have impaired transport, trafficking etc."

Smith says, "OK, but they are not dead."

Carlcotman says, "No, most NFTs, until they are extracellular, are not dead."

Junekinoshita says, "What about the tau mutation diseases?"

Smith says, "What about the French revolution?"

Smith laughs hysterically.

{PRIVATE} Cummings tells Smith "That was great !"

Junekinoshita pouts

Junekinoshita says, "I mean, wouldn't they argue against a protective role for NFTs?"

Perry says, "Yes. They are not healthy or happy. But in studies of biopsy specimens we have found that neurons with NFT actually have a more normal organization than those without NFT."

Carlcotman says, "The story there really isn't clear yet. We have a paper in press on the presence of TUNEL, BAX, and caspase 3 activation in Frontal temporal dementia (related to tau mutations)"

Paulcoleman says, "So does this aspect of the discussion suggest that neurons sacrifice some functions to maintain others?"

Smith says, "No....much as mutations in APP do not argue for A beta...but that's another discussion."

Perry says, "Paul, I think you have the essence of my argument here. The neurons sacrifice function for life."

Carlcotman says, "To Paul: perhaps neurons may be making a series of compromises"

{PRIVATE} Cummings tells Smith "Blasphemer!"

Paulcoleman says, "George I like the way you put that."

Smith says, "We all agree...lets hug"

Junekinoshita says, "But why would the rest of the body let a neuron get away with that --being a no-good freeloader, consuming resources while doing nothing?"

Junekinoshita hugs back

Smith says, "Because it wants the neuron to live."

Carlcotman says, "live and fight another day."

Smith says, "I prefer a manky arm to no arm at all."

Perry says, "Because the alternative is even worse. How can the brain function without neurons? I think the program that the neurons use in AD are those that are successful compensatory changes of acute problems."

Junekinoshita says, "We're beyond the end of the hour. Any final remarks?"

Carlcotman says, "So, Paul, have we reached a resolution, at least in terms of clarifying the issues?"

Junekinoshita says, "I'll be posting a transcript, so you all can respond in greater detail later on."

Paulcoleman says, "It appears time is drawing to a close. I would like to comment that I think much of the discussion would be clarified if we had a clearer picture of the molecular cascades involved."

Smith says, "Paul...bang on."

Carlcotman says, "One of the real values of a hypothesis is that it can be tested, and indeed the apoptosis hypothesis has been a productive one and continues to have many directions to pursue."

Smith says, "Great....some agreement but enough differences to make life bearable"

Carlcotman says, "Great line Smith!"

Cummings nods solemnly.

Perry says, "In AD, the choices available for the neurons is death or zombie status. In early life, when the fundamental abnormality may resolve itself, this zombie status may have a protective role. In AD it may not make that much of a difference in brain function."

Carlcotman says, "Bye all, thanks for the debate."

Smith says, "Thanks fore the memories!"

Cummings waves goodbye

Paulcoleman says, "Great to chat with you all"

Smith says, "Who won?"

Smith says, "Perry...let's wait them out."

Perry says, "Bye!"

Paulcoleman says, "It's how you play the game."

Smith says, "What...you turncoat."

Carlcotman leaves.

Smith says, "One down."

Paulcoleman says, "Another..."

Smith says, "Ok.....gone."

Junekinoshita says, "Bye! Thanks to all of you for participating in this very lively discussion!"

Perry says, "Thank you June."

Smith leaves.

Dr_jekyl leaves.

Paulaleigh leaves.

Cummings leaves.

Perry leaves.

Melissa2 leaves.

End of transcript...but not end of discussion!!

View the panelists' responses to some preliminary questions.
Submit a question or comment to the panelists.