Two companies have each crafted transgenic mice that expressthe human gene for beta amyloid, and as they age the animalsappear to form the plaque deposits that characterize humanAlzheimer's disease.
A California Biotechnology Inc. team in Mountain View, Calif.,inserted DNA coding for the precursor protein of beta amyloid,while Miles Research Center scientists in West Haven, Conn.,used a gene construct of the beta amyloid protein itself. Bothnow have colonies of mice that transmit and express thehuman gene constructs.
Cal Bio reported today in Nature, while the Miles findings willappear tomorrow in Science.
Scientists from each group would not characterize their mousemodel as better, but said both models will serve to clarifywhether beta amyloid is indeed responsible for the dementia ofAlzheimer's and should aid testing of therapeutics.
"They are two different experiments, with advantages to each,"Barbara Cordell, vice president of research at Cal Bio, toldBioWorld. "Ours, although preliminary, might tell us about themechanisms" by which amyloid accumulates to form plaques inthe brain.
On the other hand, Cordell said, producing amyloid itself inmice can directly address whether the protein causes neuronsto die, without the confounding presence of the precursorportions of the amyloid molecule.
Previously, only aging apes and monkeys could provide ananimal model of the degenerative disease. Mice age to theequivalent of 80 human years in just two years, so thoseexpressing the human protein and forming amyloid depositswill soon be ready for behavioral tests to see if they becomeimpaired, both companies said.
Research has yet to settle the controversy over whether theprotein deposits are causative or merely correlative to nervecell loss and behavioral decline.
Beta amyloid is processed from a precursor, and normallyneither accumulates. Cal Bio scientists have shown that brainsof Alzheimer's patients have relatively higher levels of oneform of the precursor, called APP751, than of another form,APP695. This finding led the company to select a geneconstruct directing APP751 synthesis for insertion into themouse genome.
Cal Bio's transgenic mice generated higher than normal levelsof APP751, and also formed amyloid deposits resembling thoseseen in early stages of human plaque formation. Cal Bioresearchers said they hope to see the formation of matureamyloid plaques as their transgenic mice age.
Miles scientists are watching their mice to see if the betaamyloid deposits they found in the hippocampal area of thebrain at one year spread to include the cortex. Both areas arecrucial to memory and learning.
The Cal Bio mice had preamyloid deposits of amyloid protein inboth cortex and hippocampus, but the number of mice testedwas too small to determine the age at which the deposits firstappeared.
"We will start looking for dramatic neuropathology as the miceage," said Michael Kamarck, vice president for biologicalsresearch at the Miles Research Center, "and behavioral testingis under way."
Miles will use the mice for preclinical testing of candidateAlzheimer's drugs. Miles Inc., the parent company based inElkhart, Ind., has one potential compound in clinical trials thatis unrelated to the transgenic research at its West Havenresearch center.
Cal Bio has already sent some of its mice to its Japanesepartner, Daiichi Seiyaku Co. Ltd., to test potential Alzheimer'stherapeutics. Under a 1988 agreement, Cal Bio and Daiichi willshare U.S. and Canadian marketing rights to products resultingfrom Cal Bio's research into the amyloid protein. Daiichi willhave marketing rights for the rest of the world.
Both companies intend to protect their mice by patent.
-- Roberta Friedman, Ph.D. Special to BioWorld
(c) 1997 American Health Consultants. All rights reserved.