Gene therapy boosts protein, clears mice of Alzheimer's disease plaque

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Gene therapy for Alzheimer's disease

Scientists say a one time gene therapy treatment might help clear toxic proteins that cause Alzheimer's disease, given in the early stages. The treatment boosts a protein that removed amyloid beta plaque from mouse brains bred to develop the disease.

Parkin gene destroys amyloid plaque associated with Alzheimer's disease

The findings, published in Human Molecular Genetics, suggests injecting extra parkin genes could clear the brain of the amyloid particles that destroy brain neurons in Alzheimer's disease. The researchers say it is a matter of removing garbage protein.

The parkin gene is part of a group of proteins that when mutated can lead to early Parkinson's disease and play a role in the degradation of other proteins. In the current study, the researchers showed the parkin gene degrades the amyloid beta protein.

According to Charbel E-H Moussa, M.B., Ph.D., lead author of the study from Georgetown University Medical Center, .."we are the first to show that this gene attacks amyloid beta inside brain cells for degradation." He explains the gene therapy is designed to attack Alzheimer's disease early on. The therapy might also work for other neurodegenerative brain disorders.

For the study Moussa's team used a mouse model that mimics the early stages of Alzheimer's disease by delivering an inactive HIV lentivirus into the motor cortex of the mouse brains. Doing so caused amyloid plaque to form inside the neurons, but not outside the cells. The hypothesis is that once amyloid builds inside the cells, the neurons burst leading to amyloid protein clumping and plaque between the brain cells.

Dr. Moussa has previously found a link between Alzheimer's, Parkinsonism, dementia with Lewy bodies (DLB) and Down's syndrome, all of which share the same evidence of amyloid plaque buildup in the brain tissue.


The mice, bred to develop amyloid plaque inside the neurons at age six months an outside the cells 3 to six months
later, were injected with the parkin protein on one side of the brain, leaving the other untouched as a control. The scientists found the treatment worked to clean up aberrant proteins that were then recycled - a process known as ubiquitination.

Another that cleared the mice of the Alzheimer's producing plaque in the study was through autophagy that is a form of self destruction of damaged mitochondria, the building block of cells. Moussa noted the importance of autophagy because damaged mitochondria can clog the inside of neurons.

The team found the boosting the parkin gene cleared the brain of Alzheimer's producing plaque. "With a normal amount of parkin, the cells are overwhelmed and cannot remove molecular debris. Extra parkin cleans everything," Moussa says.

In a separate experiment, the researchers compared mice not treated with the gene to those given parkin genes through the lentivirus. Compared to the non-treatment group, the gene therapy mice had 75 percent less amyloid beta plaque in the brain and an equal amount of neuronal cell preservation.

The hope is that the protein gene therapy can treat early Alzheimer's disease in humans, or stop the disease from progression when diagnosed late. The scientists say they have proven the treatment is safe, and the next step is to test it on humans. In the study, the parkin gene cleared away enough amyloid beta plaque in the brain that the researchers say regaining memory might be possible even after damage has occurred.

Hum. Mol. Genet: (2011)doi: 10.1093/hmg/ddr091

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