By David N. Leff

People affected by Alzheimer's disease (AD) are treading water in a sea of uncertainty.

First, as our population ages, there are individuals who, growing older, worry whether they may be acquiring AD.

Second, the families of near and dear relatives with failing memory and other signs of senility confront years of caring for, and coping with, members who may or may not be coming down with AD, the one form of senile dementia for which there is no therapy.

Third, neurologists must diagnose AD by applying their clinical expertise and experience, knowing that the only true authentication of the disease is postmortem autopsy of the brain.

Finally, the victim afflicted with full-blown and progressing AD is perhaps the last to feel concern for his ailment, of which he or she may be only dimly and occasionally aware.

There is one island of certainty in these treacherous currents of AD's unpredictability.

Every child born with Down's syndrome (DS) — one in 500 to 600 live births — will, without exception, go on to acquire AD in early adulthood.

DS is readily recognized at birth by its characteristic facial and physical features, as well as marked mental retardation. But the definitive diagnostic — and prognostic — marker is a third chromosome 21 in its cells. This trisomy is specific to the DS disorder.

Humans are normally endowed with 46 chromosomes, arranged in 22 numbered, matched pairs (one from each parent), plus X and Y sex-determining chromosomes.

As a Down's child grows up, the hallmarks of Alzheimer's disease set in during his or her late 20s, 30s or 40s. Amyloid plaques occur around the brain cells; neurofibrillary tangles emerge within those neurons, and the amyloid precursor protein (APP) that makes the telltale amyloid increase. These cerebral developments are the same as those found, at postmortem, in the brains of non-Down's Alzheimer's persons.

Neuroscientist Huntington Potter, at Harvard University Medical School, in Cambridge, Mass., reasoned some years ago: "Since all DS individuals have three copies of chromosome 21 in all of their cells, and they all get AD, there may be some other forms of AD that might also be due to three copies of 21 in just some of their cells."

Trisomies in the spread-sheet of human chromosomes are the result, Potter pointed out, "of mistakes in chromosome segregation." This is the process of mitosis, by which when a cell divides, it duplicates all its chromosomes and deals them out equally between its two daughter cells.

Potter predicted that two proteins known to be implicated in AD, presenilin 1 and presenilin 2 (see BioWorld Today, Jan. 3, 1997, p. 1), "might be in the cell nucleus, and involved in chromosome segregation. When one of these proteins was mutated," he added, "there would be a potential non-disjunction of the separating daughter chromosomes, or some other chromosome segregation-inducing problem."

Mutant Presenilins Make Mitosis Mess Up

The genes for these virtually identical presenilin proteins, which are present in every single cell of the body, reside on different human chromosomes: presenilin 1 on chromosome 14 and presenilin 2 on chromosome 1. "And there are whole series of families," Potter pointed out, "that develop familial Alzheimer's disease due to mutations in presenilin 1 or 2."

Potter is principal author of a paper in the current issue of Cell, dated Sept. 5, 1997, which bears the title: "Alzheimer presenilins in the nuclear membrane, interphase kinetochores and centrosomes suggest a role in chromosome segregation."

"The chromosomes are very carefully organized on the inner surface of the nuclear membrane during most of the cell's life," he explained, adding, "Then when they go into mitosis, they come away from that membrane, duplicate and segregate."

One prediction confirmed by the research the Cell paper supports, he pointed out, "is that presenilins are receptors, which connect the chromosomes to the nuclear membrane. It seems to do that," he said, "through a complex of proteins called the kinetochore, which binds to the centromere of the chromosome and is used to drag the chromosome around during mitosis."

He continued: "During the times when the cell is not dividing, the chromosomes are happily organized on the inner surface of the nuclear membrane, where we think the kinetochore performs an organizing function."

As he and his co-authors described, they used antibodies to determine the exact location of the presenilins in those areas of the cell responsible for chromosome segregation. "The interpretation that we take from these localization studies," Potter went on, "is that when they are mutant and cause AD, they probably have a defect in these processes. It doesn't prove it yet," he said, "but it's extremely suggestive that the very first step in that pathogenic AD pathway may be improper chromosome segregation."

This, of course, is the pathogenic process that gives rise to the chromosome 21 trisomy of Down's syndrome.

"Cells that have the wrong number of chromosomes," Potter pointed out, "usually have an internal cell-death mechanism called apoptosis, whereby they commit suicide. And that would lead directly to some of the cell death in the AD brain.

Wrong Number Leads To Down's, Alzheimer's

"The other thing that we know is that three copies of chromosome 21, instead of two, always leads to AD in DS. The interesting thing about that is that the amyloid precursor protein gene is on chromosome 21. So you have an increase in the amount of amyloid deposited in the brain, and increased apoptosis, because amyloid is toxic."

Advancing old age, Potter explained, is also an AD risk factor, because "the chromosome-segregation mistakes are going to occur with a certain frequency every time the cell divides. And the more it divides, the more chances the mistake will happen."

The Harvard neuroscientist said, "The main implication in our findings so far is that this is the first new indication of what the presenilins do. That opens up a whole new approach to developing therapies for Alzheimer's disease. Namely, what we're doing now is looking for ways to help the presenilins carry out their functions in the cell correctly, rather than incorrectly.

"There are a number of drug screens," he continued, "that can be designed in which the cells change their phenotypes if they have the wrong number of chromosomes. Then we'll screen combinatorial libraries for compounds that reverse the deficit in the cells carrying a presenilin mutant gene."

Potter concluded: "We're going to focus on AD first, and if we develop drugs that help the cells segregate their chromosomes correctly in AD, the approach may also be useful for other diseases in which chromosome segregation seems to be a problem — like cancer." *