Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice

Endogenous metals may contribute to the accumulation of amyloid plaques in Alzheimer's disease. To specifically examine the role of synaptic zinc in the plaque accumulation, Tg2576 (also called APP2576) transgenic mice (hAPP(+)) expressing cerebral amyloid plaque pathology were crossed with mice lacking zinc transporter 3 (ZnT3(−/−)), which is required for zinc transport into synaptic vesicles. With aging, female hAPP(+):ZnT3(+/+) mice manifested higher levels of synaptic zinc, insoluble amyloid β, and plaques than males; these sex differences disappeared in hAPP(+):ZnT3(−/−) mice. Both sexes of hAPP(+):ZnT3(−/−) mice had markedly reduced plaque load and less insoluble amyloid β compared with hAPP(+):ZnT3(+/+) mice. Hence, of endogenous metals, synaptic zinc contributes predominantly to amyloid deposition in hAPP(+) mice.