Nobody dies of Alzheimer's disease. The inexorable disintegration ofmental functions, especially memory and cognition, is not in itselffatal. Death comes from other causes, such as pneumonia, foodsuffocation or a fall, to which a patient is exposed.
Nor can any superannuated victim of senile dementia be diagnosed aspositively afflicted with Alzheimer's disease, rather than other look-alike neurological disorders. The only sure verdict requires a post-mortem brain biopsy.
What the neuropathologist then sees that clinches an Alzheimer'sdisease finding are the telltale amyloid plaques that are now the focusof research into the disease.
As well they might be. As our population grows older, Alzheimer'sdisease is the third largest medical problem in the U.S., led only bycardiovascular disease and cancer. Alzheimer's afflicts an estimated4 million Americans, at an annual health care cost of $50 billion _and still counting. It's predicted that Alzheimer's disease willescalate dramatically in the near future, as the baby-boomergeneration ages.
With no sure diagnosis during a patient's life, with no effectivetreatment, this malady cries out for a small, short-lived animal modelthat mimics not only the amyloid plaques in the aged brain, but theaccompanying behavioral degeneration.
Molecular Biologist Barbara Cordell directs the Alzheimer DiseaseCollaborative Program at Scios Nova Inc., of Mountain View, Calif."Ours is the first animal model that shows the multiple features, inparticular the behavior deficits, of Alzheimer's disease."
She and her collaborators in California and France describe theirAlzheimer's disease-mimicking mice in today's issue of Proceedingsof the National Academy of Sciences (PNAS), and titled: "Age-related learning deficits in transgenic mice expressing the 751-aminoacid isoform of human b-amyloid precursor protein."
`First And Only' Behavioral Alzheimer's Disease Model
To Cordell's knowledge, the only other Alzheimer's animal model"that comes close" is the Athena mouse, made by AthenaNeurosciences Inc., of South San Francisco. "It has amyloiddeposition, but has yet to show more than that feature of the disease,"she said.
The transgenic mouse that Scios Nova built, and Marion MerrellDow Research Institute in Strasbourg, France tested, displays the lossof memory and cognition that marks human Alzheimer's diseasevictims with advancing age.
Scios Nova seeded two genes into the genomes of their pseudo-Alzheimer's disease rodents. One transgene encoded human b-amyloid precursor protein (b-APP), which gives rise to the b-AP4peptide, widely thought to be the principal perpetrator of Alzheimer'sdisease plaques and pathogenesis.
The second cDNA sequence served as a promoter for the first gene.
The second-generation transgenic progeny, Cordell pointed out, "arephysically identical to the wild-type control animals. There's no wayto discern which is which by looking at them."
All of the rodents received secret identification in the form of tinyrandom ear-notches, before Cordell's group shipped them off toStrasbourg for mental testing.
"There," she said," they put these animals through 11 differentblinded behavioral evaluations, including circadian rhythm, motorcoordination, anxiety, and of course cognitive studies."
From this curriculum, here are a few typical "behavior-101" courses:
* String test: Mice were placed midway along a 50-cm tightrope andrated as to (0) falls off; (1) hangs onto string by two fore paws; (2)tries to climb onto string; (3) does so by two fore paws plus one orboth hind paws; (4) hangs on by all four paws, plus tail wrappedaround string; (5) escape, by working its way to one support.
* Rotarod: Mouse repeatedly placed on motor-driven cylinder,rotating at 26 times per minute. Rated by number of times it fell off in60 seconds.
* Plus-maze test: A cross-shaped maze resembling a plus sign, inwhich animals scurry from arm to arm.
* Symmetrical Y-maze: Mice allowed to explore freely, andspontaneous alternations rated.
* Water maze: An 80-cm black cylindrical pool has a 6-cm diameterwire mesh platform hidden just below the water surface. Trainingsessions teach mice how to swim to platform, using spatialnavigational cues visible to them in the room, such as windows,plants or doors, and to test memory after platform is removed.
Transgenic Mice Fail At 12 Months
In all tests, by and large, all mice (controls and transgenics) didequally well, with one exception: By the time transgenics reached theripe rodent age of 12 months, they fell down severely on memory,cognition and curiosity, as measured by the curriculum.
On the cross-shaped maze, for instance, Cordell recalled, "theanimals run from arm to arm; they like to explore the new arm. It'ssheer curiosity," she explained; "they typically want to go to a newplace, except the transgenics, who can't remember what's new andwhat was old. They tend to go back to the same arm they've alreadybeen in."
In the water maze, 12-month-old wild-type mice searched around theformer platform location site, while transgenics of same age swamrandomly around the pool.
She continued: "We saw that as the animal got older, the memory andlearning impairments became more severe. We were quite excitedabout this, because that is the living feature of Alzheimer's disease."
Her major plan, "in conjunction with Merrell-Dow, is to use thesemice in our drug development program." We will test our activecompounds in this model before proceeding to clinical trials."
Their pharmacological strategy is "to focus on developing goodinhibitors to the enzymes that form b-amyloid. This approach," sheadded, "is shared by other competitors." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.