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Scientists transform Alzheimer’s genes into healthy ones by ‘cutting out’ DNA

Alzheimer’s disease could be reversed with gene therapy, a new study has shown.

Scientists have discovered that a gene that causes the build-up of amyloid beta proteins that clog the brain can be rendered harmless by a genetic ‘snipping’.

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In experiments using a dementia patient’s own cells, the defective gene variant APOE4 was turned into the healthy APOE3 version using the technique, known as gene editing, by the team at the Massachusetts Institute of Technology.  

The discovery sheds fresh light on the age-related brain disease and could offer hope of better treatments.

Turning a gene common in those with Alzheimer’s disease, APOE4, into the healthy version, APOE3, stopped the production of a protein that smothers neurons, causing memory loss and confusion, a new study has found

APOE transports fatty molecules, such as cholesterol, into the lymph system and then into the blood. It comes in three variants, known as 2, 3, and 4.  

Among the general population, about eight percent of people have APOE2, 78 percent have APOE3, and 14 percent have APOE4. 

The APOE2 gene variant reduce their risk of Alzheimer’s by 50 percent. People with this gene experiences less of a loss of neurons although the exact mechanisms are not understood. 

But the researchers found that the profile was very different when it came to people with late-onset Alzheimer’s.

Only four percent have APOE2, 60 percent have APOE3 and 37 percent of patients carry the APOE4 gene.

Having one copy of the APOE4 gene doubles a person’s risk of Alzheimer’s, while having two copies increases it 12 times. 

Around one in four people are carriers for the dangerous gene variant, which is tested for in people who are believe to have the disease.

‘APOE4 is by far the most significant risk gene for late-onset, sporadic Alzheimer’s disease,’ said senior author Professor Li-Huei Tsai of the Massachusetts Institute of Technology.

‘However, despite that, there really has not been a whole lot of research done on it. We still don’t have a very good idea of why APOE4 increases the disease risk.’ 

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Alzheimer’s disease is a progressive brain disorder that slowly destroys memory, thinking skills and the ability to perform simple tasks.

It is the cause of 60 percent to 70 percent of cases of dementia.

The majority of people with Alzheimer’s are age 65 and older.

More than five million Americans have Alzheimer’s.

It is unknown what causes Alzheimer’s. Those who have the APOE gene are more likely to develop late-onset Alzheimer’s.

 Signs and symptoms:

  • Difficulty remembering newly learned information
  • Disorientation
  • Mood and behavioral changes
  • Suspicion about family, friends and professional caregivers
  • More serious memory loss
  • Difficulty with speaking, swallowing and walking

Stage of Alzheimer’s:

  • Mild Alzheimer’s (early-stage) – A person may be able to function independently but is having memory lapses
  • Moderate Alzheimer’s (middle-stage) – Typically the longest stage, the person may confuse words, get frustrated or angry, or have sudden behavioral changes
  • Severe Alzheimer’s disease (late-stage) – In the final stage, individuals lose the ability to respond to their environment, carry on a conversation and, eventually, control movement

There is no known cure for Alzheimer’s, but experts suggest physical exercise, social interaction and adding brain boosting omega-3 fats to your diet to prevent or slowdown the onset of symptoms.

Previous studies have shown that people with the APOE4 gene have higher levels of amyloid proteins, but little is known about why that is. 

This is one of the rogue proteins believed to be responsible for dementia by forming plaques that smother and destroy neurons, leading to loss of memory and confusion. 

An estimated 5.7 million Americans of all ages are living with Alzheimer’s disease in 2018. 

Sufferers experience a decline n cognitive, behavioral and physical abilities and there is currently no cure.

The researchers used human induced pluripotent stem cells – stem cells derived from skin or other cell types – and turned them into neurons, astrocytes and microglia, which are three different types of brain cells.

Gene editing uses bacteria like a pair of ‘molecular scissors’ to snip the unwanted gene out and replace it with a good one. 

The team changed the healthy genes to the unhealthy ones before changing them back again. 

Using the gene-editing system CRISPR/Cas9, the researchers genetically converted APOE3 in stem cells from someone without the disease to APOE4.

Because the cells were genetically identical except for the APOE gene, any differences seen between them could be attributed to that gene.  

In APOE4 astrocytes, the researchers found that cholesterol metabolism was highly disregulated.

The cells produced twice as much cholesterol as APOE3 astrocytes, and their ability to remove amyloid proteins from their surroundings was dramatically impaired.    

Microglia were similarly affected. These cells, whose normal function is to help remove foreign matter including amyloid proteins and pathogens such as bacteria, became much slower at this task when they had the APOE4 gene.  

The researchers also found they could reverse most of these effects by using CRISPR/Cas9 to convert the APOE4 gene to APOE3.

Prof Tsai and her colleagues achieved this in brain cells derived from the stem cells of a patient with late-onset Alzheimer’s disease.

In another experiment, the researchers created three-dimensional miniature brains, from cells with genes that are known to cause early-onset Alzheimer’s. 

The brains had high levels of amyloid proteins with where then expose to microglia cells, containing APOE3 and APOE4.

When exposed to APOE3 microglia, most of the amyloid proteins were cleared away, but, by contrast, APOE4 microglia did not efficiently clear them away. 

Prof Tsai said she believes APOE4 may disrupt specific signaling pathways within brain cells, leading to the changes in cell behavior seen in the study.

The findings also suggest if gene-editing technology could be made to work in humans, which many biotechnology companies are now trying to achieve, it could offer a way to treat Alzheimer’s patients who carry the APOE4 gene. 



Read more at DailyMail.co.uk


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