Pigs with genetic defects offer new avenues for Alzheimer’s treatment

Summary: New research on cloned pigs with 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 disorder.

source: Aarhus University

For decades, researchers from 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 swarm of small animals that could lead to a major step forward in the research and treatment of Alzheimer’s disease.

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

Because of the genetic mutation, pigs show signs of Alzheimer’s disease at an early age. This gives researchers an opportunity to follow early signs of the disease, as pigs show changes in the same biomarkers used for diagnosis in humans.

“By following the changes over time in pigs, we can better understand early changes in cells. Later, these changes lead to irreversible changes in the brain that cause dementia.”

“But we can now follow pigs before they lose their memory, change their behavior, etc., which makes it possible to test new drugs that can be used at an early stage to prevent Alzheimer’s disease associated with SORL1,” says Associate Professor Olaf Michael Andersen, first author. For a study that has just been published in the scientific journal Medicine Cell Reports.

“Pigs are similar to humans in many ways, which is why this increases the odds of producing drugs that will work against Alzheimer’s disease. It is important to have a working animal model to bridge the gap between research and drug development,” he explains.

Pig cloning of skin cells

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

Through extensive research over the past 20 years, it has now been conclusively demonstrated that a mutation in a fourth gene, namely SORL1, can also directly cause the widespread dementia disorder. If this gene is defective, the person who carries the genetic defect will develop Alzheimer’s disease.

We created an animal model of Alzheimer’s disease in minipigs by altering one of 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 could provide researchers with better possibilities to understand early changes in the brains of people who will later develop Alzheimer’s,” says Olaf Michael Andersen.

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

This shows a diagram of the study
Because of the genetic mutation, pigs show signs of Alzheimer’s disease at an early age. credit: researchers

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

The result is the reconstruction of the embryo, that is, a cloned egg, which develops into a new individual with the same genetic characteristics as a genetically modified skin cell. This means that young clones are born with a defective SORL1 gene.

“Pigs are similar to Alzheimer’s patients who have SORL1 genetic defects – unlike previous pig models of Alzheimer’s disease, which contained one or more mutated human genes in the hope of accelerating the disease,” says Associate Professor Charlotte Brandt Sorensen, who was responsible for developing the cloned pigs. Transgenic.

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

He can test drugs before disease appears

Professor Olaf Michael Andersen says the study has key perspectives.

“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, exactly the earliest changes occur in the brain cells of the animals we dared hope for. This makes it possible to find the indications vitals that reflect the initial, preclinical stage of the disease, he says.

The Danish company Ellegaard Göttingen Minipigs owns and raises the rights to the breed of pigs.

“The best thing is to develop new drugs based on this pig model, and we are already well ahead of the preparations. The group of patients who carry mutations in SORL1 is much larger than the group of patients who have errors in the other three known genes,” says Olaf Michael Andersen.

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About this genetics and Alzheimer’s research news

author: press office
source: Aarhus University
Contact: Press office – Aarhus University
picture: The image is attributed to the researchers

original search: open access.
A genetically engineered minipig model of Alzheimer’s disease with SORL1 heploinsufficiency deficiency.Written by Olaf M Andersen et al. Medicine Cell Reports


Summary

A genetically engineered minipig model of Alzheimer’s disease with SORL1 heploinsufficiency deficiency.

Highlights

  • Minipig model of Alzheimer’s disease by CRISPR knockout of the causal gene SORL1
  • guy SORL1 Heat phenocopy minipigs: a profile of preclinical CSF biomarkers for individuals with Alzheimer’s disease
  • SORL1 Individual insufficiency causes hyperplasia of endosomes similar to Alzheimer’s neurodegenerative disease
  • The minipig model bridges the translational gap between AD mouse models and affected individuals

Summary

Proven causative genes in Alzheimer’s disease (AD), ApplicationAnd the PSEN1And the PSEN2, Functionally characterized by the use of biomarkers, capture in vivo Profile that reflects the initial preclinical stage of the disease.

mutations in SORL1encoding the endogenous recycling receptor SORLA, was found in 2% – 3% of individuals with early-onset Alzheimer’s disease, and SORL1 Individual inadequacy appears to be a cause of Alzheimer’s disease.

To test whether SORL1 can function as a causal gene for Alzheimer’s disease, we use CRISPR-Cas9-based gene editing to develop a model SORL1 Efficiency of individual Gottingen minipigs, taking advantage of pig models for biomarker investigations.

SORL1 Individuality adequacy in young adult minipigs was found for a preclinical phenomenon in vivo Profile of AD observed with ApplicationAnd the PSEN1And the PSEN2resulting in elevated levels of amyloid beta (Aβ) and tau that precede amyloid plaque formation and neurodegeneration, as observed in humans.

Our study provides functional support for the theory that SORL1 Individual adequacy leads to endogenous cytopathology with biofluidic markers of Alzheimer’s disease autosomal dominant.

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