Mutations in the amyloid-β protein precursor gene (AβPP), the presenilin 1 gene (PSEN1) or the presenilin 2 gene (PSEN2) that increase production of the AβPP-derived peptide Aβ42 cause early-onset Alzheimer's disease. Rodent models of the disease show that further increase in Aβ42 production and earlier brain pathology can be obtained by coexpressing AβPP and PSEN1 mutations. To generate such elevated Aβ42 level in a large animal model, we produced Göttingen minipigs carrying in their genome one copy of a human PSEN1 cDNA with the Met146Ile (PSEN1M146I) mutation and three copies of a human AβPP695 cDNA with the Lys670Asn/Met671Leu (AβPPsw) double-mutation. Both transgenes were expressed in fibroblasts and in the brain, and their respective proteins were processed normally. Immunohistochemical staining with Aβ42-specific antibodies detected intraneuronal accumulation of Aβ42 in brains from a 10- and an 18-month-old pig. Such accumulation may represent an early event in the pathogenesis of Alzheimer's disease.

The role of metals in biologic systems is manifold, and understanding their behaviour in bodily processes, especially those relating to neurodegenerative diseases, is at the forefront of medical science. The function(s) of metals - such as the transition metals - and their utility in both the diagnosis and treatment of diseases in human beings, is often examined via the characterization of their distribution in animal models, with porcine models considered exceptional proxies for human physiology. To this end, we have investigated the homeostatic distribution of numerous metals (Mg, K, Ca, Mn, Fe, Cu, Zn, Rb and Mo), the non-metal P, and Zn isotopes in the organs and blood (red blood cells, plasma) of Göttingen minipigs. These results represent the first set of data outlining the homeostatic distribution of metals and Zn isotopes in Göttingen minipigs, and indicate a relatively homogeneous distribution of alkali/alkaline earth metals and P among the organs, with generally lower levels in the blood, while indicating more heterogeneous and systematic abundance patterns for transition metals. In general, the distribution of all elements analysed is similar to that found in humans. Our elemental abundance data, together with data reported for humans in the literature, suggest that element-to-element ratios, e.g. Cu/Mg, show potential as simple diagnostics for diseases such as Alzheimer's. Isotopic data indicate a heterogeneous distribution of Zn isotopes among the organs and blood, with the liver, heart and brain being the most depleted in heavy Zn isotopes, and the blood the most enriched, consistent with observations in other animal models and humans. The Zn isotopic composition of Göttingen minipigs displays a systematic offset towards lighter δ66Zn values relative to mice and sheep models, suggesting physiology that is more closely aligned with that of humans. Cumulatively, these observations strongly suggest that Göttingen minipigs are an excellent animal model for translational research involving metals, and these data provide a strong foundation for future research.

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