LONDON — Pharmacologists now have a new strategy to exploit in their attempts to develop novel therapies for Alzheimer's disease, with the arrival of a spanking new piece of the jigsaw puzzle relating to the biochemistry of this condition.

In an illuminating study, Belgian and German researchers have identified a gene that, once inhibited, may reduce the harmful accumulation of a substance in the brain which many scientists believe is responsible for the symptoms of Alzheimer's.

Up to 95 percent of people with Alzheimer's disease have no family history of the condition, and little is known about the cause of the disease in this group. In the remainder, however, the disease runs in families.

Scientists expect that by studying the genes involved and the role of their protein products in brain physiology, they will be able to develop a therapy for both the familial and sporadic forms of the disease.

Alzheimer's disease is difficult to diagnose while the patient is still alive, but postmortem studies show typical changes in the brain. One of these is the accumulation of amyloid plaques. The plaques are mainly composed of amyloid peptide, which is a breakdown product of amyloid precursor protein.

To date, studies have identified three genes which play an important role in familial cases of Alzheimer's disease. They are the gene for amyloid precursor protein itself, on chromosome 21, and the presenilin 1 and presenilin 2 genes on chromosomes 14 and 1, respectively. Point mutations in each of these genes all cause an increase in the production of amyloid peptide — although no one knew how the presenilin gene products exerted their influence.

Now, Bart De Strooper of the Flemish Institute for Biotechnology at the Center for Human Genetics, in Leuven, Belgium, and Paul Saftig, of the Centre for Biochemistry and Molecular Cell Biology at the University of Gottingen, in Germany, have elucidated one of the links between the presenilin 1 gene product and the accumulation of amyloid peptide. They report their study in a letter to Nature, Jan. 22, 1998, titled "Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein."

De Strooper, Saftig and their colleagues were working with mice in which the presenilin 1 gene had been knocked out. Unfortunately, these mice die before birth, at about 14 days' gestation. However, the two researchers decided to study neurons from the brains of the knockout embryos, which they found could be cultured just as easily as those from wild-type animals.

In the mouse, normal processing of amyloid precursor protein gives rise to only very few molecules of amyloid peptide, whereas in the human, many molecules of amyloid peptide result. For this reason, it was important for the researchers to study the processing of the human molecule. To allow them to do this, they infected the cultured neurons with a recombinant virus which induced expression of human amyloid precursor protein in these cells.

De Strooper told BioWorld International, "We found to our surprise that there was a very selective effect on the processing of amyloid precursor protein in the neurons from the presenilin 1 knockout embryos. Production of amyloid peptide was five times lower than normal."

They went on to study this phenomenon in more detail. A series of enzymes is responsible for the cleavage of amyloid precursor protein, although none of these has been identified. These enzymes are called secretases and there are at least three of them: a-, b- and g-secretase. De Strooper and Saftig found that in the neurons from the presenilin 1 knockout embryos, the a and b cleavages occurred as normal, but the g cleavage was greatly reduced.

De Strooper said: "This discovery is very important for our understanding of Alzheimer's disease, because it fits two or more pieces in the complex puzzle of this condition. For the first time, we get a clear link between the two major genetic causes of Alzheimer's disease and show that the products of both genes are involved in the same pathway. This also suggests very strongly, in my opinion, that the same pathway is relevant for the sporadic form of the disease."

The most exciting implication from the work is, however, the one which requires the most caution. De Strooper suggested that if it were possible to down-regulate the expression of the presenilin 1 gene in the adult brain, this would probably reduce the production of amyloid peptide.

He added: "If you believe — as I do — that amyloid peptide production is important for amyloid plaque formation, and that these plaques are central to the disease, then this suggests an opportunity for therapy, simply by down-regulating the presenilin 1 gene."

Potential Treatment Far From Clinic

Two important questions need to be answered first, he said. One is what happens if the g-secretase cleavage is inhibited. The result would be an accumulation of larger fragments of amyloid precursor protein, containing amyloid peptide — and no one knows whether these fragments would be benign or harmful.

Secondly, loss of presenilin-1 is lethal to the embryo, but it is not known whether its function is required by the adult brain. One way to find this out is to construct a transgenic mouse in which the presenilin 1 gene is functional until adulthood, at which point it can be knocked out — a so-called "conditional knockout".

De Strooper said: "I am very curious to learn whether anybody in the Alzheimer's disease field is making conditional knockouts of presenilin 1 — if nobody is doing it, we will have to do it."

Other work on the team's agenda includes carrying out a similar study to the one reported in Nature with knockouts of presenilin 2, and research aimed at establishing the identity of the g-secretase enzyme.

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