Synaptic Zinc Fingered As Critical In Plaque Formation

For some time, in vitro and human research has indicated that heavy metals such as zinc, copper, or iron, are critical for the aggregation of Aβ into plaques. In vivo evidence now confirms this and traces it specifically to zinc from synaptic vesicles.

In a study published in the April 30 online version of Proceedings of the National Academy of Sciences (USA), Jae-Young Koh's group at the University of Ulsan College of Medicine in Seoul, Korea, along with collaborators in the United States, crossbred mice carrying the Swedish mutant AβPP gene with mice lacking the gene for a protein that transports zinc into synaptic vesicles. As they aged, these mice showed significantly lowered amyloid plaque burdens, suggesting they have high Aβ levels but did not turn it into plaque in the absence of synaptic zinc. Furthermore, the absence of the synaptic zinc pool eliminated previous gender differences whereby female AβPP-transgenic mice had higher plaque burdens than males.

"This result from the Koh group is enormously important," said Chris Frederickson of the University of Texas Medical Branch at Galveston. "When the counter-intuitive approach of trying to block a disease process (plaque deposition) by inducing a genetic defect (the Znt3 knockout) actually works, we all must pay serious attention to the model being tested. Synaptically-released zinc emerges from this work as an undeniable, pivotal part of AD pathogenesis."—Hakon Heimer

Comments

  1. This paper provides long-awaited in vivo evidence that zinc plays a major role in cortical amyloid deposition. These workers show that mice deficient in ZnT3, a transporter required for zinc transport into synaptic vesicles, leads to markedly lowered concentrations of hippocampal zinc. When these mice were crossed with the Tg2576 AβPP-transgenic mouse model of amyloidosis there was a marked decrease in the deposition of diffuse amyloid plaques in terms of both their number and size compared with Tg2576 mice at the same age. There was a positive correlation between the level of insoluble Aβ40/42 and total zinc concentration and a negative correlation between soluble Aβ and zinc concentration. Both provide further compelling evidence that zinc plays a central role in the deposition of Aβ in the brains of AβPP transgenic mice.

    The paper supports earlier work by Bush, Huang, Atwood and Cherny showing that zinc binds avidly to Aβ and induces its precipitation in vitro, and that chelation therapy reverses amyloid deposition in AβPP-trangenic mice (see ARF news story). Although Lee et al. performed no cognitive assessments, it would be of interest to determine in future studies whether the Tg2576 AβPP-transgenic/ZnT3-knockout mice have fewer cognitive deficits compared with the reported deficits of the AβPP transgenic mice.

    View all comments by Craig Atwood

  2. This is a very interesting report demonstrating that reduced synaptic Zinc decreases Aβ plaques in the well-established Tg2576 mouse model of cerebral β-amyloidosis. The study also points to an intriguing disappearance of the usual gender disparity in plaque deposition in the synaptic zinc-deficient mice. The work does raise the question whether it is an AD-relevant zinc-Aβ interaction and/or synaptic dysfunction that is the cause of plaque decreases.

    Reports on various interventions that reduce Aβ plaques in AβPP-transgenic mice are increasing in number. These need to be accompanied by caution on what effects neuro- or synaptic toxicity may have on the development of plaques. One could predict that such damage could reduce plaques without much benefit. The discrepancy of increases in soluble Aβ versus decreases in insoluble Aβ with zinc deficiency is also being seen in other plaque-lowering studies. It is not easy to reconcile with emerging data showing that soluble Aβ increases are the best Aβ correlate of cognitive decline in Alzheimer's disease (McLean et al., 1999). This being said, this is a scientifically sound and important study that complements work by Bush, Masters, and colleagues.

    References:

    McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, Bush AI, Masters CL. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann Neurol. 1999 Dec;46(6):860-6. PubMed.

    View all comments by Gunnar Gouras

  3. After 10 years of accumulating data that implicated zinc and copper in the corruption of β-amyloid, the theory that zinc causes amyloid pathology has rapidly become validated. The current study from Dr Koh's lab gives added impetus to the growing basic data that argue very strongly that the generation of Aβ alone is not the problem in Alzheimer's disease. Lee et al. now prove that zinc release originating from the synapse is the major force behind amyloid deposition. Their data is also a mechanistic explanation for the sex differences in Alzheimer pathology.

    This theory has nothing to do with the old aluminum theory of Alzheimer's disease, and in fact there is no clear evidence that toxicological exposure to zinc plays a role in AD. Rather, the theory hinges on the age-dependent fatigue of the regulatory mechanisms that normally prevent inappropriate interaction of the brain's own abundant reservoirs of copper and zinc with Aβ. The most important aspect of this theory is that it targets therapeutics at the reversible interaction of zinc and copper with Aβ. Last year, we reported that amyloid pathology is markedly attenuated by treatment of the Tg2576 mouse model with clioquinol, a copper/zinc chelator that passes the blood-brain barrier. Treatment was accompanied by behavioral and general health benefits. This drug recently completed successful phase 2 clinical trial testing, as reported by Colin Masters at the recent 7th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy in Geneva. I am excited about the results of Lee et al. Perhaps this represents an important turning point of Alzheimer's disease research.

    View all comments by Ashley Bush

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Further Reading

Primary Papers

  1. Lee JY, Cole TB, Palmiter RD, Suh SW, Koh JY. Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice. Proc Natl Acad Sci U S A. 2002 May 28;99(11):7705-10. PubMed.

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