If we all lived to be 130 or 140 years old, we would all die ofAlzheimer's disease. Other confounding variables being equal _e.g., cancer, heart failure, homicide and suicide _ it might take thatbiblical life-span for the pathological processes that kill off neuronsin the brain to reach their ultimate endpoint.
Once neuroscientists can learn enough about those inexorable,inscrutable processes, they hope to devise drugs that will slow downthe formation of the nerve-decimating, senile neuritic plaques and neurofibrillary tangles thatmark the progression of Alzheimer's.
Today's issue of Nature reports that two normalmolecules, ubiquitous in the body, occur abnormally in Alzheimer's-sensitive regions of the brain. There, they stimulate the 42-amino-acid b-amyloid protein that causes those dementia-inducing lesions.
The article describing this new finding bears the title, "Amyloid-associated proteins a1-antichymotrypsin [ACT] and apolipoprotein E[apo E] promote assembly of Alzheimer b-proteins into filaments."
Neurobiologist Huntington Potter of Harvard Medical School is theNature paper's senior author. "Filaments," he told BioWorld, "aretoxic to neurons. If we design or search for a drug that will preventthe ACT or apoE from binding to the b-amyloid protein, that wouldhalt, or at least severely reduce, polymerization of the filaments."
Therapies In The Offing _ How Far Off?
Potter added that "some such therapeutic compounds can beimagined fairly quickly, such as peptides similar to the b-amyloidpeptide, but too short to make filaments. They would bind to thesame active site on ACT or on apoE," he explained, "andcompetitively interfere with the interaction."
An alternative therapeutic ploy would be "to reduce the formation ofACT in the brain, by various anti-inflammatory drugs." Potterdescribed "the ideal compound" as injectable into the blood stream,crossing the blood-brain barrier, and inhibiting b-amyloid depositsfrom pushing filament proliferation in the brain's hippocampus andfrontal cortex, areas where plaques and tangles grow. He hopes tohave such laboratory-tested drugs in hand "within a couple of years,"ready forclinical trials.
"Our main new finding," Potter said, "is that we showed, in vitro,that b-protein filaments don't just form spontaneously, but can betremendously promoted _ 10- to 20-fold _ by the action of whatwe call the two pathological chaperones, ACT and apoE."
Nature described one of his in vitro experiments in which "over thecourse of several days, filaments approximately seven nanometerswide, and up to many hundreds of nanometers long, steadilyincreased in number."
ACT, a1-antichymotrypsin, produced by the liver, blocks proteases,and thereby protects tissues in the body from excessive damage byinflammation. Trace ACT is also found in the healthy brain, but,Potter points out, it acts up abnormally by over-expressing only inthe Alzheimer's-associated cerebral regions.
ApoE, the 299-amino-acid apolipoprotein, is best known for its rolein trafficking cholesterol in the human body. One of its genevariants, apoE-4, has recently been linked to late-onset Alzheimer'sdisease. Which, Potter observes, "probably explains why people whoinherit two copies of the apoE-4 gene are at a higher risk thannormal."
He elaborates: "ApoE is a very interesting gene, because it's onchromosome 19, in exactly the region where there's an apparentfamilial locus for late onset Alzheimer's. And when apoE-4, an alleleof this gene on chromosome 19, and a fairly rare one, is present in anindividual, it confers a large risk of developing Alzheimer's.
"This gene cannot be called a cause," Potter cautioned, "becausesome people get Alzheimer's without it, and some who have themutant form are perfectly normal. But our results in vitro indicate amechanism by which this can be explained, namely, apoE-4 is a verygood amyloid-promoting factor."
`Weird New Chaperones'
Potter's paper links both of these good-guy proteins turned bad,apoE-4 and ACT, to the Alzheimer's disease process, by what hecalls their "weird new pathological function of chaperoning" b-amyloid's pro-filamentactivity.
Next on the Harvard neuroscientist's agenda are three projects:"First, we'd like to find out whether these pathological chaperonesincrease b-amyloid's toxicity in culture, as you would expect.
"Second, get these two proteins together to form filaments in vivo, inan experimental animal, and see if that kills neurons. Third, wewould like to begin to search for drugs that would interfere with thisreaction." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.