Too much of a good thing can be a worse curse than not enough _especially when it happens to a human chromosome.
Babies born with Down's syndrome (DS) owe their physicalanomalies and mental retardation to an inherited third chromosome21, a trisomy, added on to the normal pair bequeathed them fromtheir two parents.
Beneath the visible stigmata of DS _ round skull, flat wide face,slanted eyes, low-set ears, enlarged lips and tongue _ lurk graverorganic malformations of heart and/or kidneys.
Compounding these morphological misfortunes is severe mentalretardation. And finally, as Down's children progress to adulthood,they begin to lose brain cells in their 30s, and inexorably falls prey toAlzheimer's disease around 40 to 50 years of age.
So an animal model that faithfully mimicked the progression of DSsymptoms in its brain and body would be a double boon toneuroscientists, as a surrogate for both DS and AD.
Next Tuesday, molecular neurologist David Holtzman, ofWashington University in St. Louis, will report to the ongoingmeeting of the Society for Neuroscience in Washington, D.C., on"Developmental abnormalities and accelerated brain aging in amouse model of Down syndrome."
This presentation virtually replicates his paper in the currentProceedings of the National Academy of Sciences (PNAS), datedNov. 12, 1996. Its title: "Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome."
A decade ago, the Jackson Laboratory in Bar Harbor, Maine, raisednaturally aberrant mice with a trisomy of their chromosome 16 _ themurine counterpart of human chromosome 21. That model triplicatedthe total length of the entire aberrant chromosome, and those micedied at birth.
So mouse geneticist Muriel Davisson, at the Jackson Lab, dissectedout the tip of mouse 16's long arm, an "obligate DS region"containing all in a row _ actually, three rows _ the genes mostrelevant to the DS and AD genetic disorders. It's this "partialtrisomy" mouse model that Holtzman is reporting at the neurosciencemeeting and in the PNAS.
"Muriel had a working relationship with our group," Holtzman toldBioWorld Today, "which was at the University of California in SanFrancisco at that time. We raised a huge colony of those partial-trisomy animals, and began to do our study."
Interrogating The Murine Witnesses
That research project asked those animals to answer two sets ofquestions: One _ how well did they reproduce the developingdeterioration of cognition chacteristic of DS and AD? Two _ howdid their genes and brain anatomy relate to those behavioral patterns?
By and large, those partial-trisomy mice lived about as long as theirnormal littermates _ two years. Like human DS cases, only thefemales were fertile.
Like those humans, the mice developed more slowly than normalones. Pups took twice as long as controls to find their mothers on theother side of a cage, for example. And adult mice couldn't learn thewhereabouts of an under-water platform.
"That water-maze test," Holtzman observed, "is a very nice way toassess spatial memory, because all animals don't like to tread water.They love to get out of the pool. By recalling just visual cues in aroom, they have to be able to find that platform hidden in a tank ofwater."
What makes this proficiency trial relevant to AD, he pointed out, "isthat in lower animals, like rodents, the parts of the brain that are verysimilar to humans are in the limbic system. The parts that expand asyou go to higher animals have more to do with the cerebral cortex."
Holtzman explained that "Cholinergic neurons are a group of nervecells in a part of the limbic system called the basal forebrain. Theysecrete acetylcholine, a major neurotransmitter, which is also felt toplay a role in learning and memory. This particular group of cellsdegenerates in AD.
"In normal mice," he continued, "that system is almost identical tohumans. And in the partial trisomies, that's what we showeddegenerating."
In the brains of human AD victims, the defining hallmarks of theirdisease are senile amyloid plaques and neurofibrillary tangles. Amutated gene called amyloid precursor protein (APP) deposits thoseplaques around susceptible AD and DS neurons.
Mice Deny Plaques' Fatal AD Link
The mouse equivalent of that gene, App, is the first of the genes linedup at the tips of those three partial trisomies. "But those plaques andtangles are not found in the brains of these animals," Holtzman said," even though they over-express that defective protein, three copiesof it, as in DS."
He went on: "The paradox there is that although they don't expressplaques or tangles, they still have signs of damage in the brain. Itbrings up several issues, such as: Is beta-amyloid depositionnecessary for AD neurodegeneration altogether? That's an importantquestion, which we're now looking into."
Holtzman suggested other genes in that "obligate DS region" may bemore important than beta-amyloid for causing the ADneuropathology. One such might well be Sod, which expresses super-oxide dismutase. "No one knows what the effect of having threecopies of that might be," he observed.
"People have made transgenic mice, which express only Sod. Someof their studies suggest it can be neuroprotective, by detoxifying freeradicals. Others say it might be bad, because it produces hydrogenperoxide, another free radical.
"And if you have a mutation in that Sod gene," he added, "you getanother form of neurodegenerative disease _ amyotrophic lateralsclerosis."
One gene that encodes a risk-factor protein in AD is apolipoprotein E(apoE), one form of which accelerates dementia. It's not a part of themurine chromosome 16 partial trisomy, but rather resides on mousechromosome 7. There, with only two copies of 7, that mouse over-expresses apoE .
"What I read into that finding," Holtzman observed, "is that it'sprobably due to the fact that astrocytes or glial cells in the mouse-model brain are becoming activated. And apoE is made in astrocytes.So it might suggest that those cells are reacting to the fact that thebrain is degenerating.
"A lot of the work we are doing in our lab right now," he concluded,"is trying to understand how ApoE acts as a risk factor. We hope tomodel that question in these animals in the near future. Then we canaddress potential ways to reverse that risk by devising potentialtreatments, whatever they may be." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.