Targeting A Key Enzyme With Gene Therapy Reversed Course Of Alzheimer's Disease In Mouse Models

"What we are showing is a proof of principle that stopping thesynthesis of a protein that is necessary for the formation of thetelltale plaques reverses the progression of the disease, and moreimportantly, the cognitive function of these mice, which had alreadybeen impaired, has now recovered," says Inder Verma, professor in theLaboratory for Genetics at the Salk Institute for Biological Studies.

The findings, which are the result of a close collaborationbetween researchers at the Salk Institute and scientists at theUniversity of California in San Diego, are reported in an advanceon-line publication of Nature Neuroscience.

In the past, gene therapy has been mainly used to delivernormal genes into cells to compensate for defective versions of thegene causing disease. In their study, the researchers used gene therapyto silence a normally functioning gene. Exploiting a mechanism calledRNA interference, they were able to turn down the gene that helpsproduce the characteristic amyloid plaques that are one of thehallmarks of Alzheimer's disease.

"Within a month of treatment, mice that had already sufferedmemory deficits could learn and remember how to find their way througha water maze," says co-author Robert Marr, a post-doctoral researcherin Verma's lab.

"It appears that these mice can come back from a very severelevel of disease progression," adds first author Oded Singer, also atthe Salk. "This is a very important finding because humans are usuallydiagnosed when the disease has already progressed relatively far."

But he warns that it is too early to make direct comparisonswith the human disease, since mice ordinarily don't develop thesymptoms of the disease unless they are genetically engineered to doso.

Amyloid plaques, which are insoluble protein clumps in thebrain, can precede the onset of dementia by many years. These plaquesare formed when enzymes cleave the amyloid precursor protein (APP)releasing the toxic beta amyloid fragments that clump together to formthe sticky plaques. One of the enzymes doing the cleaving is calledbeta secretase or BACE1.

And although the production of beta amyloid occurs in allbrains, healthy brains are able to clear away excess amounts. Brains ofpeople with Alzheimer's disease, on the other hand, are unable tocontrol beta amyloid accumulation.

For several years now, drug companies have been trying to finda drug that inhibits BACE1 and thus prevent beta amyloid from buildingup in brains of people with Alzheimer's disease. But so far, the goalhas remained elusive.

Instead of looking for chemical compounds to inhibit BACE1,Oded Singer, collaborating with the laboratories of Fred H. Gage at theSalk Institute and lead author Eliezer Masliah at UCSD, resorted tosmall biological molecules, called short interfering RNA, or siRNA,which derail the process of translating genes into proteins. They worklike a dimmer switch, reducing the amount of available gene product, inthis 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 thatwere producing vast amounts of human beta-amyloid and whose brainswhere littered with plaques.

"When you compare the brains of treated and untreated mice, thedifference is striking. Silencing BACE1 reduced the number and size ofplaques by two thirds within a month, which is incredibly fast," saysSinger.

Co-authors of this work also include Edward Rockenstein and Leslie Crews, both at UCSD.

Alzheimer's disease is a progressive neurodegenerative disorderand the most common cause of dementia among the elderly in the UnitedStates, affecting 4.5-5 million adults - 10 times more than thoseaffected by Parkinson's disease. Starting with mild memory problems andending with severe brain damage, Alzheimer's usually begins after theage of 60, the risk increasing with age.

The Salk Institute for Biological Studies in La Jolla, California,is an independent nonprofit organization dedicated to fundamentaldiscoveries in the life sciences, the improvement of human health andthe training of future generations of researchers. Jonas Salk, M.D.,whose polio vaccine all but eradicated the crippling diseasepoliomyelitis in 1955, opened the Institute in 1965 with a gift of landfrom the City of San Diego and the financial support of the March ofDimes.