BioWorld International Correspondent

LONDON - An enzyme that plays a key role in the generation of amyloid beta-peptide in Alzheimer's disease - making it a promising target for novel therapies to treat the condition - turns out to have an important role in nerve myelination.

The discovery means that those working on any therapy that aims to inhibit that enzyme now will know where to look for potential side effects.

Christian Haass, professor of biochemistry at the Adolf Butenandt-Institute at Ludwig-Maximilians-University in Munich, Germany, told BioWorld International: "Some reports about this work have suggested that this is bad news, but I think it is good news. I am not at all sure that administering therapies that inhibit this enzyme would cause demyelination in the adult brain. But those developing such treatments will now be able to look at the animals they have tested these substances on, to see what the effects are."

The work is reported in the Sept. 21, 2006, online publication of Sciencexpress in a paper titled "Control of Peripheral Nerve Myelination by the Beta-Secretase BACE1."

In Alzheimer's disease, a protein found in the membranes of neurons called amyloid precursor protein (APP) is broken down to form amyloid beta-peptide. The latter accumulates in the brain, forming plaques.

A series of enzymes cleaves the membrane-bound APP before amyloid beta-peptide is released into the extracellular space. Action by beta-secretase is needed first, followed by a reaction brought about by gamma-secretase. The specific enzyme that brings about the beta-secretase reaction is a type I transmembrane aspartyl protease called BACE1 (beta-site APP cleaving enzyme).

Scientists know that BACE1 is the only beta-secretase involved in the reaction because knockout mice lacking functional copies of the gene encoding BACE1 make no amyloid beta-peptide. Yet little was known about the normal role of BACE1. When three researchers carried out targeted mutation of the gene for BACE1 in mice, they reported that the animals' behavior was virtually normal.

Haass and his colleagues, however, earlier had knocked out BACE1 in zebra fish and found that the fish had a movement abnormality. Hass was not convinced that loss of BACE1 was without effect. He said: "It is simply not the case that a highly conserved enzyme has no function except to cause trouble in a disease such as Alzheimer's."

So the team decided to investigate where and when in the brain BACE1 is expressed. Their investigations showed that the peak in manufacture of the enzyme in the brains of mice is in the early postnatal period - exactly the same time when the protective Schwann cells, which sheath the neurons, are becoming myelinated.

During the development and myelination of Schwann cells, a molecule produced by neuronal axons called type III neuregulin 1 (NRG1) plays an important role by activating receptors on the Schwann cells.

Earlier studies already had shown that if signalling by type III NRG1 was weak, or if the corresponding receptors on the Schwann cells were absent, neuronal axons failed to become properly sheathed by the Schwann cells and were under-myelinated. Conversely, if type III NRG1 was overexpressed, the myelin layers on the nerve cells became thicker than normal.

Further investigations by Haass and his team confirmed that BACE1 and type III NRG were expressed in the same brain tissues. The pattern of expression of BACE1 in spinal cord and dorsal route ganglion was very similar to that of type III NRG.

Next, the researchers studied the myelination of the sciatic nerve in mice lacking functional copies of the gene encoding BACE1, using electron microscopy. Those studies showed that the axons of the knockout mice had significantly less myelin than axons of control mice, and many axons surrounded by single Schwann cells had completely failed to become myelinated. Overall, the changes were similar to those of mice lacking normal levels of NRG1, and to those of mice lacking the Schwann cell receptors on which NRG1 acts.

Additional experiments showed that in the BACE1 knockout mice, NRG1 protein accumulated, and that this was due to the loss of BACE1.

Haass concluded that work in the area will continue apace, now that two main streams of interest - Alzheimer's disease and the signalling pathways involved in nerve cell myelination - have been brought together.

His future agenda will include looking at the effects of absence of BACE1 in the central nervous system of mice. His collaborators, Alistair Garratt and Carmen Birchmeier, of the Max-Delbruck-Center for Molecular Medicine, in Berlin, also have mice lacking functional copies of the gene encoding type III NRG1. Those animals already have been crossed with BACE1 knockout mice - and Haass said the resulting phenotype is "striking."

"We will be writing this up soon," he said.

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