Alzheimer's disease first surfaces as increased forgetfulness,essentially the inability to form new memories. Then a morefrightening memory loss occurs: the names and identities of friendsand family members disappear. Finally, simple daily tasks such asgoing to the store, become impossible. Yet sufferers live on, oftenfor many years, totally incapacitated.

Alzheimer's disease primarily effects the aged. With the percentageof the world's population that is over 65 years old growing rapidly,this prolonged disease promises to be a significant health careproblem for the foreseeable future. Already, specialized Alzheimer'scare units are opening in increasing numbers in U.S. nursing homes.But while the unmet need for effective therapeutics is tremendousand research and development spending has been increasing apace,the complexity of the neurological disorder has moved scientists tosearch for Alzheimer's underlying cause.

A major obstacle to finding the disease's cause has been the lack ofan animal model system. Finally, as detailed in today's issue ofNature, a transgenic mouse model that shows the amyloid proteinplaques characteristic of Alzheimer's disease has become available.In an article entitled "Alzheimer-type neuropathology in transgenicmice overexpressing V717F a-amyloid precursor protein," Leadauthor Dora Games, of Athena Neurosciences Inc., and colleaguesreport on their development of this new transgenic mouse and how itdiffers from previous attempts to create a useful model.

These researchers inserted a human a-amyloid precursor proteingene containing a mutation associated with familial Alzheimer'sdisease into transgenic mice. Their construct allowed expression of a40- to 42-amino acid fragment of a-amyloid precursor protein, calledamyloid a-protein, that forms the amyloid plaques that are thehallmark of Alzheimer's disease. Using histo-chemical stainingtechniques, these scientists showed that the transgenic micecontaining this construct began to exhibit deposits of amyloidplaques in their brain tissue by six to nine months of age. At agesgreater than nine months, the density of the plaques increased to thepoint where the staining pattern resembled that of full blownAlzheimer's disease.

What's Different About Athena's Transgenics?

As senior author Ivan Lieberburg, vice president of research atAthena, in South San Francisco, told BioWorld Today, "Previouslymade Alzheimer's disease transgenics have shown only modestoverexpression of a-amyloid. The amyloid deposits seen in thesemodels are small and rare with the accompanying neuropathologybeing mild or non-existent. In contrast, the mice that we havedeveloped demonstrate robust and reproducible pathology that iseasy to quantify, and they present many of the attendantneuropathological markers of late-stage Alzheimer's disease."

The success of this new effort appears to be due to two strategiesemployed in constructing the introduced gene. First, expression ofthe human a-amyloid precursor protein minigene is driven by aplatelet-derived growth factor-a promoter. As the authors discuss,genes driven by this promoter are preferentially expressed in theneurons of substructures of the brain that are involved inAlzheimer's disease.

Second, as explained by John Hardy, a geneticist at the University ofSouth Florida, in his accompanying Nature editorial, the increasedexpression of the a-amyloid precursor protein minigene is likely dueto its being a cross between cDNA and a genomic DNA fragment.By inserting introns six, seven and eight from the a-amyloidprecursor protein gene into the cDNA, the alternative splicing of thegene product that is associated with and appears important inAlzheimer's can occur.

When BioWorld Today asked Lieberburg what Athena's next step indeveloping these mice would be, he said that "studying thebehavioral changes associated with amyloid plaque deposition is atop priority. Our plan is to collaborate closely with our colleagues atLilly whose forte is behavioral analysis. Based on the extensivepathology observed in these mice, we would expect to see severememory problems in the appropriate maze tests."

When asked if this work had begun, Lieberburg said, "Frankly, weare still in the planning stage. At present, we are consuming animalsfor our initial characterization work as fast as they can be made. Weneed some time to expand our transgenic line."

Cause Of Alzheimer's Still Controversial

However, as Hardy cautioned, while the availability of a mousemodel is crucial to advancement in therapeutic development forAlzheimer's, controversy still exists as to the underlying mechanismsresponsible. He told BioWorld, "We know that there are lots ofpotential causes. In fact, their are at least three geneticallyidentifiable associations with Alzheimer's disease: the amyloidmutation, an unidentified gene on chromosome 14, andapolipoprotein E variants found on chromosome 19." As explainedby Hardy, several schools of thought exist as to the mechanisms bywhich the disease develops. While one believes that amyloid plaquebuild-up causes the rest of the pathology seen, others are convincedthat amyloid deposition is only a secondary result of the real cause.

By itself, the development of these mice will not resolve thiscontroversy. However, their use should allow many previouslyintractable questions to be addressed. Hardy said that many of thesequestions can now be quickly answered, especially if colonies ofthese mice can be expanded and distributed to the researchcommunity. In fact, one of Athena's goals is to make them availableto other researchers, but Lieberburg explained that "we still have toformulate our policy on distribution in conjunction with Lilly."

For now, Lieberburg is encouraged by this first step. As he said,"Developing this mouse was the holy grail of Alzheimer's research.Now we can begin to unravel this disease. Finally, we have a testsystem for therapeutics so that each new potential candidate thatcomes along does not have to be tried in humans." n

-- Chester Bisbee Special To BioWorld Today

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