If you moisten a piece of metallic zinc foil, it will burst into flames. And a quantity of zinc dust, if exposed to air, also will ignite.

What this pyromaniacal metal has to do with Alzheimer’s disease (AD) is the topic of a paper in today’s Proceedings of the National Academy of Sciences (PNAS), dated April 30, 2002. Its title offers a couple of hints: “Contribution by synaptic zinc to the gender-disparate plaque formation in human . . . mutant APP transgenic mice.” Its senior author is research neurologist Jae-Young Koh, who directs the Center for the Study of Central Nervous System Zinc at the University of Ulsan in Seoul, Korea. A co-author is behavioral neurobiologist Richard Palmiter, a professor of biochemistry at the University of Washington in Seattle.

APP, of course, stands for “amyloid precursor protein,” the lengthy molecule that spawns the stubbier amyloid b peptide. This constitutes the senile neuritic plaques that are the hallmarks of AD. In fact, these plaques, which clump around the dying neurons in AD, are the visible post-mortem evidence that the deceased did in fact suffer from Alzheimer’s.

Koh told BioWorld Today: “My paper says that there is a pool of zinc in the brain called synaptic zinc. When we deleted the gene that is responsible for the accumulation of zinc in the synaptic vesicles, then we saw a great reduction of amyloid plaque burden in transgenic, AD-modeling mice. That means that synaptic zinc plays a large role in the development of mature plaques in those animals. That’s the novel bottom line of our PNAS paper.

“Its implication,” he continued, “is that we may be able to find a way to reduce plaque burden by maneuvers that interfere in the interaction between zinc and beta-amyloid peptide. Probably one can use chelating agents that bind metal tightly,” Koh went on. “Actually the group of Ashley Bush and Rudolph Tanzi [at Harvard-affiliated Massachusetts General Hospital] is trying a substance called clioquinol, which is a weak metal chelator, in reducing plaque load in transgenic mice. I think they are doing human clinical trials with that substance. They are familiar with our work as well.”

To which Palmiter added: “They gave that same zinc chelator chronically to the transgenic mice with the Alzheimer precursor protein, and had a very beneficial effect on reducing plaque burden.”

Three Mouse Strains Parse Plaque Load

To examine the relationship between zinc and AD plaque formation, Koh and his co-authors raised transgenic mice lacking the ZnT3 gene, which is required for normal transport and release of zinc into neuronal synapses of the brain’s cerebral cortex.

“To conduct our animal experiments,” Koh recounted, “we began with a transgenic mouse that overexpresses the human mutant APP gene. In this mouse a lot of plaques develop with age. We have one other knockout mouse the ZnT3 transporter gene in which synaptic zinc is lacking. So we crossbred these two mouse strains and got three genotypes plus/plus, plus/minus and minus/minus. In -/-, there is no synaptic zinc but a lot of APP expression,” Koh explained. “The +/+ mice have a lot of synaptic zinc and a lot of amyloid protein. Plus/minus is in between.

“What we found,” Koh said, summing up the experiment’s results, “is that in mice totally lacking synaptic zinc, the plaque burden decreased by about 80 percent compared to ZnT3 transporter-plus mice. So we think that synaptic zinc is very important in the development of beta-amyloid plaques in the AD-mimicking, transgenic mouse.

“Additionally,” Koh added, “we found that female mice have much more plaque burden with aging than do males. So there was a very good correlation between synaptic zinc and plaque burden. Then, when we deleted the ZnT3 transporter gene completely, the sexual difference disappeared. That means that that gender difference in development of synaptic zinc might be responsible for the sexual difference in plaque load in these mice.

“So now we are interested in exploring the mechanism of sexual difference,” Koh observed, “the sexually different development of synaptic zinc. We are currently studying that now investigating the mechanism of gender accumulation of synaptic zinc in this transgenic mouse. It may be sexual-hormone dependent.”

To measure zinc deposits in amyloid plaques, the team relied on “a traditional dye called Congo red, which identifies plaques in AD brains. So Congophilic plaques mean a very mature dense plaque, in which there is a lot of zinc inside invariably.”

A synapse is the functional membrane-to-membrane contact of one neuron with another. It transmits nerve impulses over the synaptic cleft or gap from one cell to the next via a chemical transmitter stored in synaptic vesicles round or ellipsoid vacuoles.

“Synaptic zinc,” Koh noted, “is located in a subset of terminal vesicles. In those areas they contain a very high level of zinc. Synaptic zinc is released into the extracellular space, and that might be the place where zinc and amyloid interact. It’s not very well known how bodily zinc is transported across the blood-brain barrier, and gets into the brain’s synaptic vesicles. But ultimately its origin in the body should come from oral dietary intake. There is no other source. The function of that synaptic zinc,” Koh observed, “is being studied by many investigators now. One thing is that zinc might modulate glutamate neurotransmission across the synapse. And zinc also can interfere with other neurotransmitter actions, such as GABA [gamma-aminobutyric acid], acetylcholine, etc. Zinc might be a modulator of synaptic transmission at the extracellular space.”

Wanted: Better Heavy Zinc Chelating Agents

Koh defines the next step in his research as “finding better metal chelators than the existing ones. We are looking actively for these agents synthesizing new ones and trying to find more effective ones. If synaptic zinc is very important in developing plaque, chelators might be useful in reducing the plaque load. That’s our top priority trying to find effective measures to prevent amyloid-beta plaque accumulation. Once we do, then we would plan preclinical in vivo studies with such chelators as prerequisites of human clinical trials. We really want to do that,” he concluded, “but not at the moment.”

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