Novel gene therapy shows promise against Alzheimer's

Researchers at Georgetown University Medical Center have reported that gene therapy that boosts the ability of brain cells to gobble up toxic proteins prevents development of Alzheimer's disease in mice that are predestined to develop it.

They said the treatment - which is given just once - could potentially do the same in people at the beginning stages of the disease.

They said that giving brain cells extra parkin genes promoted efficient and effective removal of amyloid particles believed to be destroying the neurons from the inside.

This revved up protein disposal process prevents the cells from dying and spewing amyloid proteins into the brain, where they stick together and clump into plaque, they added.

"At its core, this is a simple garbage in-garbage out therapy, and we are the first to show that this gene attacks amyloid beta inside brain cells for degradation," said the study's lead investigator and neuroscientist Charbel E-H Moussa.

He said that the strategy may work for other brain disorders.

"Many neurodegenerative diseases are characterised by a toxic build-up of one protein or another, and this approach is designed to prevent that process early-on," he said.

Moussa and his colleagues developed a unique model system that mimics the early stages of these diseases. They used a lentivirus, a modified, inert form of HIV, to deliver amyloid beta into the motor cortex of rats, and showed that this produced a buildup of amyloid beta inside neurons, but not an accumulation outside of the cells.

They hypothesised that once the stockpile of amyloid beta inside the cell reached a critical level, neurons burst, and the amyloid beta proteins begin to stick together in the space between brain cells, forming plaque.

Additionally, tau pathology is triggered by amyloid beta inside neurons, causing tau malfunctions, and the whole process results in increased brain inflammation.

So what Moussa and his team tested was the removal of the amyloid beta buildup inside neurons.

They used triple transgenic mice that are often used as a model of human Alzheimer's disease.

They develop intracellular amyloid beta at six months of age and extracellular amyloid beta plaque about 3-6 months later.

The researchers injected parkin in one side of the brain of young mice, and left the other side untouched, as a control to compare effects of the treatment.

They found that providing brain cells with about 50% more parkin protein activates two parallel garbage-removal processes within the brain.

One is ubiquitination, in which errant proteins are targeted for destruction and recycling within the cell.

The other process is autophagy, in which membranes form around damaged mitochondria (the cell's power plants) and these membranes fuse with lysosomes that destroys the contents.

This is particularly important, said Moussa, because damaged mitochondria have been found to clog the insides of neurons affected by Alzheimer's disease, and the extra parkin seems to help clear them. That allows the cells to produce new and healthy mitochondria.

"With a normal amount of parkin, the cells are overwhelmed and cannot remove molecular debris. Extra parkin cleans everything," he said.

In a second experiment, the researchers found that mice given parkin genes through the lentiviral vector had 75 percent less amyloid beta plaque in their brains, compared to mice that were not treated, and that neuronal cell death was also reduced by that amount.

They also showed that parkin cleared away so much amyloid beta inside cells that the function of normal glutamate neurotransmission in the hippocampus was restored.

The study is published online in Human Molecular Genetics.