Minipigs Carrying Gene Mutation Associated With Alzheimer’s Provide New Research Tool

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“Minipigs carrying a gene mutation linked to Alzheimer’s offer a new research tool”

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For decades, researchers around the world have been working hard to understand Alzheimer’s disease. Now, a collaboration between the Department of Biomedicine and the Department of Clinical Medicine at Aarhus University has resulted in a herd of mini-pigs that could lead to a major advance in Alzheimer’s research and treatment.

The cloned pigs were born with a mutation in the SORL1 gene, which is interesting because the mutations are found in up to 2-3% of all early-onset human Alzheimer’s cases.

Because of the gene mutation, the pigs develop signs of Alzheimer’s at a young age. This gives researchers the ability to track the early signs of the disease, as the pigs show changes in the same biomarkers used to diagnose humans.

“By tracking the changes over time in the pigs, we can better understand the earliest changes in the cells. Later, these changes lead to the irreversible changes in the brain that are the cause of dementia. But now we can track the pigs before they lose their memory, change their behavior, etc., which will make it possible to test new drugs that can be used at an early stage to prevent SORL1-associated Alzheimer’s disease,” says associate professor Olav Michael Andersen, the first author of the study, which has just been published in the scientific journal Cell Reports Medicine.

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“Pigs are similar to humans in many ways, so this increases the potential for manufacturing drugs to treat Alzheimer’s. It is important to have a working animal model to bridge the gap between research and drug development,” he explains.

Pigs cloned from skin cells

Since the 1990s, researchers have known of three genes that, when mutated, can directly cause Alzheimer’s disease.

Intensive research over the past 20 years has now finally proven that a mutation in a fourth gene, namely SORL1, can also directly cause the widespread dementia. If this gene is defective, the carrier of the gene defect develops Alzheimer’s disease.

“We have created an animal model of Alzheimer’s in minipigs by altering one of only four genes currently known to be directly responsible for the disease. The pigs can be used in the pharmaceutical industry to develop new drugs – while giving researchers better opportunities to understand the early changes in the brains of people who will later develop Alzheimer’s disease,” says Olav Michael Andersen.

Researchers have also previously developed pig models of Alzheimer’s and other diseases through cloning. For this purpose, the genetic material is taken from an unfertilized egg cell of a fattening pig and then fused with a skin cell of another pig.

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In this study, the researchers previously used CRISPR-Cas9-based gene editing to destroy the SORL1 gene in a skin cell taken from a Göttingen minipig.

The result is a reconstructed embryo, i.e. a cloned egg cell, which develops into a new individual with the same genetic characteristics as the genetically modified skin cell. This means that the cloned minipigs will be born with a damaged SORL1 gene.

“The pigs resemble Alzheimer’s patients with SORL1 gene defects – in contrast to previous pig models of Alzheimer’s, in which one or more mutated human genes were inserted in hopes of speeding up the disease,” says associate professor Charlotte Brandt Sørensen, who carried out this study done has been responsible for the development of genetically modified, cloned pigs.

Because the mutation is inherited, researchers can now breed pigs that show the first signs of Alzheimer’s before they are three years old.

Can test drugs before the disease breaks out

The study has great prospects, says associate professor Olav Michael Andersen.

“We know from human genetics that we develop Alzheimer’s when the SORL1 gene is destroyed. We have shown that when we destroy this gene in pigs, the very early changes in the animals’ brain cells that we had dared hope for occur. This makes it possible to find biomarkers that reflect the initial, preclinical phase of the disease,” he says.

The Danish company Ellegaard Göttingen Minipigs owns the rights to the pig variety and breeds it.

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“The best thing would be to develop new drugs based on this pig model, and we are already well advanced with the compounds. The group of patients who carry mutations in SORL1 is far larger than the group of patients who have errors in the three other known genes,” says Olav Michael Andersen.

Facts: Alzheimer’s and Genetics

  • Both hereditary and environmental factors can be at the root of Alzheimer’s disease. If there is a genetic predisposition, this enters into a complex interaction with other risk factors such as lifestyle (e.g. smoking and obesity) and environmental influences.
  • Only about 3 percent of all people with Alzheimer’s disease developed the disease as a direct result of a mutation in a known gene. The known causative genes in Alzheimer’s are: APP, PSEN1, PSEN2 – and most recently established: SORL1.
  • The SORL1 gene was identified in 1996 at Aarhus University. It was made by Dr. Philip Scheltens as the cause of Alzheimer’s disease in an article in The Lancet in 2021.
  • The study with the cloned minipigs is one of the reasons why Associate Professor Olav Michael Andersen received the Alzheimer Research Foundation Basic Research Award at the end of September 2022.

Relation: Andersen OM, Bøgh N, Landau AM, et al. A genetically modified minipig model for Alzheimer’s disease with SORL1 haploinsufficiency. Cell representative Med. 2022;3(9). doi: 10.1016/j.xcrm.2022.100740

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