"What we are showing is a proof of principle that stopping the synthesis of a protein that is necessary for the formation of the telltale plaques reverses the progression of the disease, and more importantly, the cognitive function of these mice, which had already been impaired, has now recovered," says Inder Verma, professor in the Laboratory for Genetics at the Salk Institute for Biological Studies.
The findings, which are the result of a close collaboration between researchers at the Salk Institute and scientists at the University of California in San Diego, are reported in an advance on-line publication of Nature Neuroscience.
In the past, gene therapy has been mainly used to deliver normal genes into cells to compensate for defective versions of the gene causing disease. In their study, the researchers used gene therapy to silence a normally functioning gene. Exploiting a mechanism called RNA interference, they were able to turn down the gene that helps produce the characteristic amyloid plaques that are one of the hallmarks of Alzheimer's disease.
"Within a month of treatment, mice that had already suffered memory deficits could learn and remember how to find their way through a water maze," says co-author Robert Marr, a post-doctoral researcher in Verma's lab.
"It appears that these mice can come back from a very severe level of disease progression," adds first author Oded Singer, also at the Salk. "This is a very important finding because humans are usually diagnosed when the disease has already progressed relatively far."
But he warns that it is too early to make direct comparisons with the human disease, since mice ordinarily don't develop the symptoms of the disease unless they are genetically engineered to do so.
Amyloid plaques, which are insoluble protein clumps in the brain, can precede the onset of dementia by many years. These plaques are formed when enzymes cleave the amyloid precursor protein (APP) releasing the toxic beta amyloid fragments that clump together to form the sticky plaques. One of the enzymes doing the cleaving is called beta secretase or BACE1.
And although the production of beta amyloid occurs in all brains, healthy brains are able to clear away excess amounts. Brains of people with Alzheimer's disease, on the other hand, are unable to control beta amyloid accumulation.
For several years now, drug companies have been trying to find a drug that inhibits BACE1 and thus prevent beta amyloid from building up in brains of people with Alzheimer's disease. But so far, the goal has remained elusive.
Instead of looking for chemical compounds to inhibit BACE1, Oded Singer, collaborating with the laboratories of Fred H. Gage at the Salk Institute and lead author Eliezer Masliah at UCSD, resorted to small biological molecules, called short interfering RNA, or siRNA, which derail the process of translating genes into proteins. They work like a dimmer switch, reducing the amount of available gene product, in this case the enzyme BACE1.
A modified lentivirus, which has been developed in Verma's lab, delivered the siRNAs into the brain cells of the transgenic mice that were producing vast amounts of human beta-amyloid and whose brains where littered with plaques.
"When you compare the brains of treated and untreated mice, the difference is striking. Silencing BACE1 reduced the number and size of plaques by two thirds within a month, which is incredibly fast," says Singer.
Co-authors of this work also include Edward Rockenstein and Leslie Crews, both at UCSD.
Alzheimer's disease is a progressive neurodegenerative disorder and the most common cause of dementia among the elderly in the United States, affecting 4.5-5 million adults - 10 times more than those affected by Parkinson's disease. Starting with mild memory problems and ending with severe brain damage, Alzheimer's usually begins after the age of 60, the risk increasing with age.
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