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Biotech / Medical : Neuroscience -- Ignore unavailable to you. Want to Upgrade?

To: nigel bates who wrote (37)	8/29/2000 9:11:24 AM
From: scott_jiminez	Read Replies (1) \| Respond to of 278

>>>...the relationship between aggregation-prone proteins susceptible to metal-mediated oxidative stress.<<< I'm certainly not qualified to respond to the idea of this commonality between such distinct diseases. My knee-jerk response is to put it in my shoebox of grand theories of neuropatholoogies - theories which have become more grandiose in the last decade since press releases stopped being peer reviewed (extreme sarcasm) - and return to my can of Ensure. I simply find it incredibly demeaning to patients and researchers alike that a BT will take advantage of certain publicity (the well established finding that the spread of the prion isoform associated with BVE may travel silently though other species) as an opportunity to promote their unproven approach and, moreover, to assert their platform could be equally applicable to AD, a much more lucrative disease. Let's keep in mind that after decades of concerted effort, the link between zinc, aluminum and other heavy metals and the establishment and/or progression of AD is weak at best. Let's also contemplate another highly plausible scenario for the observed redox reactions following protein (amyloid) aggregation in AD: while amyloid itself may catalyze some of the metal transitions leading to oxidative stress, IMO the response of the brain's endogenous macrophage, the microglia, is countless orders of magnitude more important. Microglia respond to the slightest perturbation in the CNS by rushing to the site and releasing a virtual who's who of potentially toxic molecules. These compounds (and, equally, the enzymes that catalyze their synthesis) can generate levels of oxidative, nitrositive, etc. stress that a more passive catalyst, such as aggregated-protein-associated metal clusters, would be very, very, very hard pressed to match. In my view, it would be substantially more valuable to modulate the microglial reaction then to attempt to abrogate protein clustering. But wouldn't some diminution in amyloid aggregation be helpful? I can't answer that; perhaps the studies are out there. However, even on a conceptual basis, it's hard to imagine the parameters of an experiment where a titration of amyloid deposits was generated (perhaps this has been achieved in some of the transgenics). And this still begs the question - oxidative-stress-generating microglia will still appear in large numbers when ANY numbers of protein aggregates form in brain and the redox potential of activated microglial products constitutes a much more serious threat than the passively catalyzed reactions of zinc, aluminum, etc.