Few pathological hallmarks are as notorious as the tangles
and plaques of Alzheimer's disease. What is especially
noxious about the two formations is the way they divide and
conquer brain cells. Tangles clog up the inside of neurons
while plaques encroach from the outside, slowly engulfing
the neuron's long, tapering limbs-the axons and dendrites.
For years, many researchers believed that tangles and plaques were formed in the brain as a result of an underlying disease mechanism-accessories to Alzheimer's rather than the direct cause. But four years ago, Dennis Selkoe, Harvard Medical School professor of neurology at Brigham and Women's Hospital, and his colleagues found that even normal human brain cells produce amyloid beta protein (A beta), the protein found in plaques. This raised the possibility that Alzheimer's disease might actually be a direct consequence of an overproduction of A beta.
Now, Selkoe and his colleague Martin Citron, assistant professor of neurology at BWH, have garnered more evidence that A beta overaccumulation is, indeed, the main culprit in Alzheimer's disease. The researchers, in collaboration with scientists in other labs, report in this month's Nature Medicine that when two mutant Alzheimer's genes, presenilin 1 (PS1) and presenilin 2 (PS2), were transfected into normal human kidney cells, production of a particular form of A beta-called A beta 42-doubled.
"Given that this occurs directly in peripheral cultured cells in the absence of the disease state, it's clear the doubling is not a secondary effect," Selkoe says. The new findings come on the heels of an earlier discovery by Selkoe and his colleague Cynthia Lemere, instructor in neurology, that Alzheimer's patients with mutant PS1 genes have double the usual level of plaques containing A beta 42 in their brains. The earlier findings were reported in the August issue of Nature Medicine.
If overproduction of A beta 42 is a cause of some forms of Alzheimer's disease, as Selkoe believes, then one strategy for fighting the disease would be to selectively turn down production of the protein. Citron and Selkoe report in the November issue of Proceedings of the National Academy of Sciences that such a strategy has been found to work for a closely related protein, A beta 40. (A beta comes in two lengths, A beta 40 and A beta 42, which differ by just two amino acids.)
Ultimately, Selkoe and his colleagues hope to prevent Alzheimer's disease as well as treat it. "My vision of the brave new world in 'Alzheimerology' is that as a part of health screening 10 years from now, you'll have your blood level of A beta 40 and A beta 42 checked," he says.
Selkoe entered the arena of A beta research by a circuitous route. To begin with, he was interested in the other half of the notorious Alzheimer's pair, tangles. But by the mid-1980s, it was becoming clear that tangles were a consequence of other factors rather than a primary cause of the disease.
Killer Plaques: During the presymptomatic stage of
Alzheimer's disease (A), A beta accumulates in diffuse
plaques. Axons and dendrites within and near the plaque
appear structurally normal. By the symptomatic stage (B),
many plaques appear "mature": A beta is particularly
aggregated (chains) and other brain proteins (white ovals)
have accumulated. Nearby microglia and astrocytes are
activated, and axons and dendrites are degenerating.
Disenchanted with tangles, Selkoe and his colleagues
set out to purify the protein constituting plaques, which
turned out to be the peptide A beta. Along the way, Selkoe
and his colleagues made a surprising discovery: A beta was
found not just in brain plaques but in skin and intestinal
deposits, too.
Intrigued by the widespread appearance of A beta, Selkoe and Michael Schlossmacher, clinical fellow in neurology, and other colleagues spent the next few years culturing cells from a variety of human organs. What they found was startling: Any cell-even the brain cells and fibroblasts of babies-secreted A beta.
"So here was a whole new concept," says Selkoe. Until then, A beta was thought to be a consequence, rather than a primary cause, of the Alzheimer's disease process. "We concluded, 'Ah, but amyloid protein is made throughout life,'" says Selkoe. Just as some forms of heart disease and stroke are due to an overabundance of cholesterol-a life- sustaining molecule-some forms of Alzheimer's disease might be the result of an upregulation of the normal production of A beta.
Meanwhile, geneticists were busy finding DNA alterations in patients suffering from familial forms of Alzheimer's disease. Two genes were implicated in the early 1990s-APP and ApoE. Another two were identified in 1995, PS1 and PS2. Lemere and Selkoe measured the density of A beta- containing plaques in the brains of patients with mutant PS1 and PS2. Sure enough, the density of plaques containing A beta 42 was twice that found in conventional Alzheimer's patients.
To see whether the mutant genes actually caused the doubling of A beta 42, Citron transfected the mutant PS1 and PS2 genes into normal human kidney cells. Weiming Xia and Jimin Zhang, research fellows in neurology, did the same in normal Chinese hamster ovary cells. At the same time, collaborators of the Selkoe lab created transgenic mice with the mutant genes. In both the transfected cells and the transgenic mice, A beta 42 was apparently double the normal level.
As evidence mounts that A beta 42 overproduction is a causative factor in some forms of Alzheimer's disease, Citron and Selkoe have been looking for ways to selectively interfere with the process. They have recently found that a compound called MDL 28170 selectively inhibits the production of A beta 40.
"If the 40 can be inhibited without inhibiting the 42, wouldn't it be wonderful if we could do the opposite-inhibit the 42?" says Selkoe. He believes that A beta-blocking drugs-whether inhibiting 40 and 42, or just 42-will go into clinical trials in the near future.
"I think the first clinical trials of these A beta blockers will begin as early, perhaps, as 1999," he says. "And in ten years, hopefully, doctors will have a whole armamentarium of anti-Alzheimer's drugs even beyond these."
-Misia Landau