A new type of gene therapy boosted the ability of brain cells to dispose of toxic proteins so plaques did not build up between cells and thereby protected mice genetically engineered to have the disease from developing Alzheimer’s, said US researchers in a new study published online this week in the journal Human Molecular Genetics.
Lead investigator, Dr Charbel E-H Moussa, a neuroscientist at Georgetown University School of Medicine in Washington DC, and colleagues hope the therapy, which gives brain cells extra parkin genes, will one day do the same for humans, who would only need one treatment in the early stages of Alzheimer’s.
Parkin is part of a complex called “ubiquitin ligase” that identifies proteins for breakdown inside cells. Mutations in parkin are known to cause an early onset inherited form of Parkinson’s disease.
Moussa and colleagues found that giving neurons extra parkin genes made them better at removing amyloid proteins thought to be destroying the brain cells from the inside. They said this prevented cells dying and spewing amyloid proteins into the spaces between the cells, where they clump into plaques, one of the hallmarks of Alzheimer’s.
Moussa told the press this was a straightforward garbage in – garbage out therapy.
“We are the first to show that this gene attacks amyloid beta inside brain cells for degradation,” he said, explaining this approach might also work for other brain disorders:
“Many neurodegenerative diseases are characterized by a toxic build-up of one protein or another, and this approach is designed to prevent that process early-on,” he added.
Moussa said more and more neuroscientists are coming round to their controversial idea that diseases like Alzheimer’s start when brain cells can’t get rid of toxic amyloid beta proteins fast enough.
He and his colleagues have published previous work where they suggest a build-up of amyloid beta links Alzheimer’s, Parkinsonism (such as Dementia with Lewy Bodies, or DLB), and Down’s syndrome.
In Parkinsonism, the toxic protein is in Lewy bodies, clumps of protein found in brains of people with DLB, and producing too much amyloid protein is also a problem for people with Down’s syndrome because they have three copies of chromosome 21, which generates amyloid.
A key feature of their work is a unique model that mimics the early stages of these diseases.
Using a modified, inert form of HIV they delivered amyloid beta protein into the motor cortex of rats’ brains and showed this led to a build up inside brain cells but not between them.
They interpreted this to mean that the amyloid levels inside the brain cells have to reach a critical threshold before the cells burst and the proteins spill out and form clumps that become plaque between the cells.
They also suggested that the other hallmark of Alzheimer’s, the “tau tangles” that form inside neurons is also triggered by amyloid beta build up.
Moussu and his team then used the same gene therapy method from this current study to get rats’ brains to express more parkin gene at the same time as giving them more amyloid beta. The parkin helped the brain cells get rid of the protein more effectively.
In this latest study, the team tested the removal of the amyloid beta build up inside the brain cells in triple transgenic mice, a lab animal often used as a model of Alzheimer’s in humans. In these mice, when they get to six months, amyloid beta starts to form inside brain cells, and starts to accumulate between brain cells about 3 to 6 months after that.
Moussu and colleagues injected the parkin into one side of the brain of the young mice, leaving the other side as a control.
They found that giving the brain cells an extra 50% more parkin activate two “garbage disposal” mechanisms that ran in parallel.
One disposal mechanism, “ubiquitination”, targets bad proteins for degradation and recycling inside the cell, while the other, “autophagy”, surrounds damaged mitochondria (the mini “power plants” that give cells energy) with a membrane that fuses them with lysosomes that digest and destroy unwanted cell materials.
Moussa said this autophagy was important because other studies have shown that damaged mitochondria seem to clog up neurons affected by Alzheimer’s, so having extra parkin probably helps get rid of them so they can produce new, healthy ones.
“With a normal amount of parkin, the cells are overwhelmed and cannot remove molecular debris. Extra parkin cleans everything,” he explained.
Moussa and colleagues did another experiment where giving mice parkin led to 75% reduction in amyloid beta protein compared to untreated mice, and this also reduced neuron death by the same amount.
In this experiment they found that the parkin also got rid of so much amyloid beta inside the cells that it restored the function of normal glutamate neurotransmission in the hippocampus, an important process for memory formation, retention and retrieval.
“Hypothetically, these damaged cells could restart memory formation,” said Moussa, adding that they have now done all the animal work needed in this type of research, in readiness for the next stage to be in humans, starting with a safety analysis.
If these same results can be proved in humans, and shown to be safe, then the aim will be to start such treatments as early as possiblie in the development of neurodegenerative diseases, said Moussa.
“Our hope is to stop the whole process early on, but if it is later, perhaps we can halt progression,” he added.
“Parkin mediates beclin-dependent autophagic clearance of defective mitochondria and ubiquitinated A[beta] in AD models.”
Preeti J. Khandelwal, Alexander M. Herman, Hyang-Sook Hoe, G. William Rebeck, and Charbel E-H Moussa.
Human Molecular Genetics, ddr091 first published online 4 March 2011
Additional source: Georgetown University Medical Center.
Written by: Catharine Paddock, PhD