Targeting a key enzyme with gene therapy reversed course of Alzheimer's disease in mouse models ( s with the human disease since mice or...)

Targeting a key enzyme with gene therapy reversed course of Alzheimer's disease in mouse models

s 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.

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Source:Salk Institute

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( s with the human disease since mice or...)Targeting a key enzyme with gene therapy reversed course of Alzheimer's disease in mouse models