Pigs with a genetic defect provide new perspectives for the treatment of Alzheimer’s

Summary: New research on cloned pigs with a SORL1 mutation sheds light on the development of Alzheimer’s. The findings could pave the way for new treatments for neurodegenerative disorder.

source: Aarhus University

For decades, researchers around the world have worked 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 flock of piglets that could lead to a major breakthrough in Alzheimer’s research and treatment.

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

Due to the genetic mutation, pigs develop signs of Alzheimer’s at a young age. This gives researchers the opportunity to follow early signs of the disease, as pigs show changes in the same biomarkers used to make the diagnosis in humans.

“By following the changes over time in pigs, we can better understand the early changes in the cells. Subsequently, these changes lead to the irreversible changes in the brain that are the cause of 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 SORL1-associated Alzheimer’s disease,” says the professor. associate Olav Michael Andersen, who is the first author of the study, just published in the scientific journal Cell brings back the medicine.

“Pigs resemble humans in many ways, which is why this increases the chances of making drugs that work to fight Alzheimer’s. It is important to have a viable animal model to bridge the gap between drug research and development, ”she explains.

Pigs cloned from skin cells

Since the 1990s, researchers have been aware of three genes that, 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 widespread dementia disorder. If this gene is defective, the person carrying the genetic defect will develop Alzheimer’s.

“We have created an animal model for Alzheimer’s in piglets 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, this can provide researchers with a better chance of understanding the early changes in the brains of people who will later develop Alzheimer’s, “says Olav Michael Andersen.

Researchers have also previously developed pig models for Alzheimer’s and other diseases using cloning. This is done by removing the hereditary material from an underused egg taken from a pig, after which the cell is fused with a skin cell from another pig.

Due to the genetic mutation, pigs develop signs of Alzheimer’s at a young age. Credit: Researchers

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

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

“Pigs resemble Alzheimer’s patients who have defects in the SORL1 gene, in contrast to previous pig models for Alzheimer’s, which had one or more mutated human genes inserted in hopes of accelerating the disease,” says the associate professor. Charlotte Brandt Sørensen, who is responsible for the development of the genetically modified and cloned pigs.

As the mutation is inherited, researchers can now breed pigs that show the first signs of Alzheimer’s before they reach the age of three.

He can test medications before the disease breaks out

The study has important prospects, says Associate Professor Olav Michael Andersen.

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

The Danish company Ellegaard Göttingen Minipigs owns the rights to the pig variety and is breeding them.

“The best thing would be to develop new drugs based on this pig model and we are already well underway with 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, “says Olav Michael Andersen.

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About this genetic and Alzheimer’s research news

Author: Press office
source: Aarhus University
Contact: Press Office – University of Aarhus
Image: The image is attributed to the researchers

Original research: Free access.
“A genetically modified minipig model for Alzheimer’s disease with haploinsufficiency SORL1” by Olav M. Andersen et al. Cell brings back the medicine


Abstract

A genetically modified minipig model for Alzheimer’s disease with haploinsufficiency SORL1

Emphasizes

  • Minipig model of Alzheimer’s disease by CRISPR knockout of the causative gene SORL1
  • young SORL1 it minipigs phenocopy a preclinical biomarker profile of the cerebrospinal fluid of individuals with AD
  • SORL1 haploinsufficiency causes enlarged endosomes similar to the neuronal pathology of AD
  • A minipig model that bridges the translational gap between mouse models of AD and affected individuals

Summary

The causal genes established in Alzheimer’s disease (AD), APP, PSEN1And PSEN2, are functionally characterized using biomarkers, capturing an in vivo profile reflecting the early preclinical stage of the disease.

Mutations inside SORL1encoding the SORLA endosome recycling receptor, are found in 2% -3% of individuals with early-onset AD and SORL1 haploinsufficiency appears to be the cause of AD.

To check if SORL1 can function as a causal gene for AD, we use CRISPR-Cas9 based gene editing to develop a model of SORL1 haploinsufficiency in Göttingen pigs, exploiting pig models for biomarker investigations.

SORL1 haploinsufficiency in young adult pigs is found to be phenocopied in the preclinical in vivo AD profile observed with APP, PSEN1And PSEN2resulting in increased β-amyloid (Aβ) and tau levels that precede amyloid plaque formation and neurodegeneration, as observed in humans.

Our study provides functional support for the theory that SORL1 haploinsufficiency leads to endosome cytopathology with hallmarks of the autosomal dominant AD biofluid.

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