Distribution of Zn isotopes during Alzheimer’s disease

Alzheimer's disease is associated with abnormal homeostasis of Zn, because of deposits of Zn-rich amyloid-β fibrils.This connection between Zn and brain aging provides a possibility to use changes in Zn homeostasis to study the evolution of the disease.Here, we studied the evolution of the Zn isotopic composition of brain, serum and red blood cells from APPswe/ PSEN1dE9 transgenic mice, which develop Alzheimer's-like disease (including Aβ deposition starting after 6 months), in comparison to wild type controls.We found that wild type brains become progressively enriched in the lighter isotopes of Zn between 6 and 12 months.We interpret this enrichment in terms of changes in Zn speciation in the cytoplasm, where isotopically heavy unbound Zn 2+ is bound to glutamate released by presynaptic vesicles of neurons.Brains from APPswe/PSEN1dE9 mice were enriched in the heavier isotopes of Zn when compared to wild type suggesting an increase in Zn content of the brain associated with Aβ plaques where Zn binds preferentially to isotopically heavy amino acids such as histidine and glutamate.