It takes two smoking guns _ one behavioral, the other, pathological_ for a neurologist to bring in a verdict of Alzheimer's disease(AD).

Gun one is the familiar symptomology in many aging men andwomen of deteriorating memory, orientation and cognition. Thetrouble with that evidence of senile dementia is it's like trying to pickout the perpetrator in a line-up of suspects. While AD is the maincause of such diminished mental capacity, it's not the only one.

But it is the only one for which there is no effective therapy.

The pathological gun consists of peptides in so-called neuriticplaques. These peptides aggregate around the brain cells of ADpatients, and are hallmarks of the disease. The key ingredient insenile neuritic plaques is human beta-amyloid (Ab) protein.

The trouble with these telltale cerebral clues, of course, is thatplaques can only be detected by postmortem analysis of thoseneurons in the brain. "Scientists who work in the pharmaceuticalindustry testing drugs," said molecular neurobiologist Karen Hsiaioof the University of Minnesota, "are trying to find drugs that caneither improve memory or behavior in Alzheimer's disease, or delaythe onset of memory loss."

Hsiaio has created a line of transgenic mice that closely mimic boththe behavioral and pathological traits of AD. Her university, she toldBioWorld Today, "is licensing the rights to these mice to the MayoClinic, our neighbor down the highway. It has a subsidiary, MayoMedical Ventures, which will be selling the animals to thepharmaceutical industry."

Hsiaio is first author of a paper in the current issue of Science, datedOct. 4, 1996, in which her AD-copycat mice make their debut. Itstitle: "Correlative memory deficits, Ab elevation, and amyloidplaques in transgenic mice."

Two rodent-raising facilities, Charles River Laboratories, ofWashington, Mass., and McLaughlin Research Institute, of GreatFalls, Mont., are growing colonies of her AD-surrogate mice, Hsiaiosaid, "expressly for the purpose of distributing them to people in thepharmaceutical industry and to academicians."

She offers to supply the latter directly, "for no charge except shippingand maintenance," but with a proviso:

"The scientists in academia must sign a document saying they willnot give the mice away to other people. They must also promise toshow the data before it's published to me and Mayo's StevenYounkin, my close collaborator and co-author in this endeavor. Andwe reserve the right to ask the researchers to repeat certainexperiments in a coded, blinded fashion. That's basically our onlystipulation, because we want only reproducible research published,with our transgenic mice."

As for her group's own continuing research, "We want to use thesemice to figure out what's fundamentally wrong with the brain in AD,and to resolve the controversy of whether neuritic plaques cause thememory loss, or whether they are just a byproduct of another process,which is causing the behavioral deficit."

Several pharmaceutical companies, she observed, have drugs able toinhibit plaque formation, "and they will be involved in ourexperiments."

In one experimental approach, she and her co-authors will use plaqueinhibitors in the transgenic mice, "to see whether they change theirbehavior for better or for worse. It's certainly possible," sheexplained, "that if you disperse the plaques, prevent them fromaggregating, the mice may not get demented. But it's also possiblethat coalescence of the plaques is a defense mechanism that the brainuses to sequester the Ab. It's conceivable that the mice could getbetter, or get worse, or that nothing will happen."

Hsiaio's transgenic mice displayed a close parallel between age-related onset of memory loss and expression of human Ab neuriticplaques in their brains.

The Science paper's senior author, cell biologist Gregory Cole,defines his scientific focus as "Alzheimerology." He is associateresearch director of the Geriatric Research, Education and ClinicalCenter at the Sepulveda Veterans Affairs Medical Center in LosAngeles.

Measuring Amyloid Output In AD Brains

"The drug companies that have been into this area for a long time,already have a number of inhibitors of aggregation and production ofAb," Cole told BioWorld Today. "And they're looking for modelsystems to test them in.

"Having the transgenics," he went on, "there's no ambiguity; you canmeasure the Ab production in the brain, which is very difficult to doif you don't have a transgenic.

"They can measure the aggregation in both mutational variants of Ab_ the 40-amino-acid and 42-amino-acid variants of the peptide _ inparticular the 42, which is thought to be the more pathogenic of thetwo.

"A number of people, our group included," Cole said, "have madeantibodies to recognize 42, not 40, and we've seen that the majorityof plaques contained largely 42.

"So the 42 becomes a drug target, and the significance of that is youmay be able to shift that percentage without causing a lot of otherside effects. Whereas if you tried to knock out Ab productionaltogether, you may be interfering with a lot of different importantprotease functions in the brain.

"So the real questions are animal-model questions: Are these drugstoxic? Can they get into the brain? Are they going to be able to havean effective dose that won't make the animal epileptic or something?All these questions are do-able.

"What remains to be seen," he concluded, "is how muchneurodegeneration you're going to get, because our mice have beenlooked at for only 12 months _ about half a mouse's average lifespan." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.