Thu Sep 25 10:55:55, 1997:

June_kinoshita says, "Hello John. Welcome! Hello Keith!"

Keith_crutcher says, "Hello June. You are holding up well!"

Kieranb says, "Hi John - thanks for agreeing to give the lecture. I have been looking over your outline and I think that it will be an interesting lecture!"

June_kinoshita says, "I should clarify what today's format will be. John has laid out the key points of his hypothesis on the lecture web page. During the coming hour, he can elaborate on it as he wishes and address questions from the audience."

Olney says, "You're welcome"

June_kinoshita says, "I suspect people will straggle in over the next little while. Why don't those of us who are now on-line introduce ourselves, and we can begin the discussion. Kieran Breen will be moderating today. Take it away, Kieran!"

June_kinoshita applauds Kieranb fervently.

Kieranb says, "Perhaps I should start. I am Kieran Breen from Dundee in Scotland."

Keith_crutcher says, "Keith Crutcher here in Cincinnati, Ohio."

June_kinoshita says, "June Kinoshita in Belmont, Mass."

Kieranb says, "Our speaker today is John Olney from the Dept. of Psychiatry in Washington University in St. Louis. John is going to talk to us about a new excitotoxic hypothesis for AD. John, if you want to start by outlining your theory, and then we can join in and ask questions when appreopriate."

Olney says, "As we have outlined in our slides we believe that the work we are conducting on the neurotoxic potential of NMDA receptor underfunctioning could provide insight into the mechanism by which neurons are killed in AD. We believe that this process (called NMDA receptor hypofunction -- NRHypo) might be responsible for NFTs. NRHypo is present in normal brain and worsens as the brain ages. What differentiates a normal person from one with AD is that a patient with AD has other abnormalities that will exacerbate the NRHypo state. One of the additional abnormalities would be amylodosis."

Keith_crutcher says, "So do you think that these additional abnormalities are simply accelerating the normal effect of aging? And if you lived long enough, everyone would show the same neurodegenerative pathology?"

Olney says, "Yes to such an extent that it exceeds a threshold necessary for triggering widespread corticolimbic neurodegeneration."

Kieranb says, "John, have any studies been done on the pathology of mice who are null for the NMDA-Receptor?"

Olney says [responding to Keith Crutcher], "No not necessarily because amyloidopathy and the other factors are not extensively present in normals. It would be a matter of degree and rate of onset."

Keith_crutcher says, "I was also wondering how you think the time course of the NRHypo effect compares with the rate of progression of AD pathology?"

Olney says, "I not aware of any studies to date. Remember though that we are not postulating that ALL NMDA receptors are hypoactive in the aged, just the subset that are found in the critical circuits which mediate the neurotoxicity."

Kieranb says, "Do I understand your hypothesis correctly in that the hypoactive receptors are, in fact, hypersensitive?"

Olney says, "As we have outlined in our lecture pages the mechanism by which neurons are killed is one of disinhibition, which releases a complex excitotocity."

Olney says, "Kieranb, No what we are saying that early on the NMDA receptors are hypersensitive. The neurons bearing these NMDA receptors are thus selectively killed by Glu and amyloid acting in concert. In this way NMDA receptors and their neurons are selectively killed in the brain."

Keith_crutcher says, "I am a little confused. Are you postulating that individual receptors lose sensitivity or that there is a reduction in neuronal sensitivity due to loss of receptors?"

Olney says, "The end result is thus a NRHypo state. The NRHypo state would then begin to kill other neurons through this disinhibited circuit mechanism. It's complicated."

Kieranb says, "John, surely this will lead to a therapeutic paradox. In the early stages, you want to dampen the NMDA response, and in the later, you want to augment it! How do you decide which drugs to give?"

Olney says, "You are correct! The problem in directly augmenting NMDA receptors is that this has a great chance of killing neurons"

Keith_crutcher says, "Dr. Olney, I don't know if you saw my earlier question. I am trying to understand if your mechanism involves decreased sensitivity of individual receptors (changes in affinity) or reductions in receptor number."

Olney says, "We would propose the following:"

Olney says, "keith, I'll get back to your question in a second."

Keith_crutcher says, "No rush."

Olney says, "There are 2 stages in the neurodegenerative process. Very early on, NMDA antagonists would be therapeutic, but they should be used together with "safener" agents that protect against NRHypo-induced neurodegeneration. In the later (symptomatic) stages only the "safener" agents should be used. Safener" aghents would be those that we have shown to protect against NRHypo-induced neurotoxicity in rat brain. An abreviated list can be found in the Table."

Olney says, "Keith, I'm composing my response to you now."

Keith_crutcher nods at Olney.

Olney says, "We are not talking about decreased sensitivity. We are talking about loss of function due to loss of receptors."

Kieranb says, " John, that is a wide variety of drugs acting at a large number of receptors. The problem with them, I suspect, would be non-specific effects. Have you tried any partial agonists which would block high endogenous NMDA but act as agonists with low endogenous levels?"

Olney says, "I assume you may be thinking of glycine site agents. We have not studied, nor had access to such agents as you describe."

Kieranb says, "They may be interesting to try as they may obviate the need for a precise diagnosis of the endogenous NMDA status."

Olney says, "I would agree."

Olney says, "You're welcome."

Olney says, "Since there are no more questions, I guess we will call it quits."

Olney says, "Thank you for coming."

June_kinoshita says, "Thank you so much!"

June_kinoshita applauds Olney fervently.

Kieranb says, "Thanks John for a very interesting session - you certainly have stimulated a lot of discussion."

Kieranb applauds fervently.

Olney smiles at Kieranb.

Olney smiles at June_kinoshita.

Olney smiles at S_lloyd.

S_lloyd says, "Is the poster chat at noon for the Newcastle Lewy body poster?"

Kieranb says, "Yes, it is in the poster hall, starting any time now!"