Background: Preclinical animal models are essential for the development of effective treatments. For instance, the 5xFAD mouse model successfully represents the pathophysiology of Alzheimer's disease (AD). Expression of humanized APP (K670N/M671L - Swedish, I716V - Florida, V717I - London) and PSEN1 (M146L and L286V), found in early onset AD patients, induces the production of amyloid-β 42 (Aβ42) and amyloid deposition, gliosis, and progressive neuronal loss. While these mouse models are necessary to identify mechanisms of the disease progression, translating the findings by using large animal models such as pigs allows us to explore treatments under clinical conditions, and therefore, improve the success of clinical trial outcomes. For example, the gray-to-white matter ratio and the complexity of the distribution of crossing fibers in the pig brain is more similar to humans than are rodents.
Method: Phenotypes of previous swine models carrying humanized APP and PSEN1 to mimic the 5xFAD mouse model did not align with the mouse model, presumably due to differences in aging rates or variation in the expression level of the genes. To accelerate the impact of the humanized APP and PSEN1, we first inactivated endogenous porcine APP and PSEN1 genes by using the CRISPR/Cas9 system in fetal fibroblast cells. Subsequently, constructs designed to express human APP and PSEN1 under the control of the neuron specific Thy1 promoter were transfected into the cells. Cells carrying the humanized APP and PSEN1 genes and the cells were used for somatic cell nuclear transfer to produce AD swine model.
Result: Thirteen piglets were born from a single pregnant sow and the genotyping of the piglets indicated that the piglets carried inactivated porcine APP and PSEN1 and carry humanized APP/PSEN1 as expected. Immunohistochemistry on the brain of the newborn AD piglets revealed an elevated abundance of Aβ42 compared to the wild type.
Conclusion: Production of the novel AD swine model will offer a new pre-clinical animal resource to expand our understanding of Alzheimer's disease pathogenesis and develop effective treatments against the disease.
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Integrative multiomics reveals common endotypes across PSEN1, PSEN2, and APP mutations in familial Alzheimer's disease.
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