Summary: New research on cloned pigs carrying a mutation in SORL1 sheds light on the development of Alzheimer’s disease. The findings could pave the way for new treatments for the neurodegenerative disease.
Source: Aarhus University
For decades, researchers around the world have worked hard to understand Alzheimer’s disease. Today, a collaboration between the Department of Biomedicine and the Department of Clinical Medicine at Aarhus University has resulted in a herd of minipigs that could lead to a major breakthrough in the research and treatment of Alzheimer’s disease .
The cloned pigs were born with a mutation in the SORL1 gene, which is interesting because mutations are found in up to 2-3% of all cases of early Alzheimer’s in humans.
Due to the genetic mutation, pigs develop signs of Alzheimer’s at a young age. This gives researchers the opportunity to track early signs of disease, as pigs show changes in the same biomarkers that are used to make the diagnosis in humans.
“By tracking changes over time in pigs, we can better understand early changes in cells. Later, these changes lead to irreversible brain damage that causes dementia.
“But now we can track pigs before they lose their memory, change their behavior, etc., which will allow testing of new drugs that can be used at an early stage to prevent Alzheimer’s disease associated with SORL1”, explains the associate professor. Olav Michael Andersen, who is the first author of the study, which has just been published in the scientific journal The cell brings back the medicine.
“Pigs resemble humans in many ways, which is why it increases the possibilities of producing drugs that will work against Alzheimer’s disease. It is important to have a workable animal model to bridge the gap between drug research and development,” he explains.
Pigs cloned from skin cells
Since the 1990s, researchers have known of three genes which, if mutated, can directly cause Alzheimer’s disease.
Through intense research over the past 20 years, it has now been definitively established that a mutation in a fourth gene, namely SORL1, can also directly cause the widespread dementia disorder. If this gene is defective, the person carrying the genetic defect will develop Alzheimer’s disease.
“We have created an animal model for Alzheimer’s disease in minipigs by modifying one of the four genes currently known to be directly responsible for the disease. Pigs can be used in the pharmaceutical industry to develop new drugs, and at the same time it can provide researchers with better opportunities to understand early changes in the brains of people who later develop Alzheimer’s disease.” explains Olav Michael Andersen.
Researchers have also previously developed porcine models for Alzheimer’s disease and other diseases through cloning. This is done by removing hereditary material from an underutilized egg taken from a pig, after which the cell is fused with a skin cell from another pig.
In this study, the researchers had previously used CRISPR-Cas9-based gene editing to knock out the SORL1 gene in a skin cell taken from a minipig of the Göttingen breed.
The result is a reconstructed embryo, ie a cloned egg, which develops into a new individual with the same genetic characteristics as the genetically modified skin cell. This means that cloned minipigs are born with a damaged SORL1 gene.
“Pigs resemble Alzheimer’s disease patients who have the defects in the SORL1 gene, unlike previous pig models for Alzheimer’s disease, which had one or more mutated human genes inserted in the hope of accelerating the disease,” says Associate Professor Charlotte Brandt Sørensen, who has been responsible for the development of genetically modified and cloned pigs.
Since the mutation is inherited, researchers can now breed pigs that show the first signs of Alzheimer’s disease before the age of three.
Can test drugs before illness breaks out
The study has major insights, says Associate Professor Olav Michael Andersen.
“We know from human genetics that when the SORL1 gene is destroyed, we develop Alzheimer’s disease. We have shown that if we destroy this gene in pigs, the very first changes in the animals’ brain cells occur that we had dared to hope for. 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 them.
“The best would be to develop new drugs based on this porcine model, and we are already well advanced in the preparations. The group of patients who carry SORL1 mutations is much larger than the group of patients who have errors in the other three known genes,” explains Olav Michael Andersen.
About this genetics and Alzheimer’s disease research news
Author: Press office
Source: Aarhus University
Contact: Press Office – Aarhus University
Image: The image is attributed to the researchers
Original research: Free access.
“A Genetically Engineered Minipig Model for Alzheimer’s Disease with SORL1 Haploinsufficiency” by Olav M. Andersen et al. Medicine Reports Unit
A genetically engineered mini-pig model for Alzheimer’s disease with SORL1 haploinsufficiency
- Minipig model of Alzheimer’s disease by CRISPR knockout of the causative gene SORL1
- Young SORL1 he minipigs phenocopy a preclinical profile of CSF biomarkers in people with Alzheimer’s disease
- SORL1 haploinsufficiency causes enlarged endosomes similar to the neuronal pathology of Alzheimer’s disease
- A minipig model bridging the translational gap between AD mouse models and affected individuals
Causal genes established in Alzheimer’s disease (AD), APPLICATION, DOG1and PSEN2, are functionally characterized using biomarkers, capturing a live profile reflecting the initial preclinical phase of the disease.
Mutations in SORL1encoding the endosome recycling receptor SORLA, are found in 2% to 3% of people with early Alzheimer’s disease, and SORL1 haploinsufficiency appears to be the cause of AD.
To test if SORL1 may function as a causative gene for Alzheimer’s disease, we are using CRISPR-Cas9-based gene editing to develop a model of SORL1 haploinsufficiency in Göttingen minipigs, taking advantage of porcine models for biomarker research.
SORL1 haploinsufficiency in young adult minipigs found to phenocopy preclinical live AD profile observed with APPLICATION, DOG1and PSEN2resulting in elevated levels of β-amyloid (Aβ) and tau preceding amyloid plaque formation and neurodegeneration, as seen in humans.
Our study provides functional support for the theory that SORL1 haploinsufficiency leads to endosome cytopathology with biofluid characteristics of autosomal dominant AD.
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