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Alzheimer's enzyme important for myelin

Beta-secretase enzyme involved in Alzheimer's pathology is required for peripheral nerve myelination

By | September 22, 2006

An enzyme involved in Alzheimer's disease also contributes to myelination of peripheral nerves, according to a study in this week in Science. Inhibitors of this enzyme, called beta-Secretase, are considered to be prime candidates for Alzheimer's treatment, so the enzyme's role in myelination may have implications for potential side effects of these drugs, the authors say. "It's a mild cautionary note to those who are developing the beta-secretase drugs," said Robert Vassar of Northwestern University in Evanston, Ill., who was not involved in the study. In Alzheimer's disease, amyloid beta (Aß) peptide accumulates in the brain. A beta-secretase enzyme called BACE1 (ß-site APP cleaving enzyme-1) is required for Aß synthesis; in BACE knockout mice, no Aß peptide is produced . Although BACE1's role in Alzheimer's is fairly well-established, not much is known about the enzyme's possible role in normal physiology, said study senior author Christian Haass of Ludwig-Maximilians-University in Münich. Led by Michael Willem, also of Ludwig-Maximilians-University, the researchers found that BACE1 expression is highest in postnatal mice when neurons are becoming coated in myelin. The researchers also found that the pattern of BACE1 expression in the peripheral nervous system is very similar to that of neuregulin 1, a factor uknown to be important for myelination. Using electron microscopy, the researchers found that the myelin surrounding the peripheral nerves in BACE1 knockouts is abnormally thin. They also found that unprocessed neuregulin 1 accumulates in BACE1 knockout animals, indicating that BACE1 is likely required for neuregulin 1 to myelinate axons normally. Based on these results, "BACE clearly plays a very important role in development, particularly in controlling the myelin sheath thickness," said Philip Wong of Johns Hopkins University in Baltimore, who was not involved in the study. The finding "came as a big surprise to all of us," Haass told The Scientist in an email. Since Aß peptides cannot be synthesized in the absence of beta-secretase activity, many researchers are hopeful that inhibitors of beta-secretases may be effective in treating Alzheimer's disease. Beta-secretase inhibitors blocking nerve myelination should not be a problem in adult patients, Wong said, as long as BACE1 is not responsible for maintenance of the myelin sheath. It's possible that a problem could arise if a patient taking beta-secretase inhibitors for Alzheimer's disease sustained a peripheral nerve injury, Vassar said. Based on the study's findings, the drugs might prevent injured nerves from repairing myelin. "It's something to be aware of" when beta-secretase inhibitors are tested in clinical trials, Vassar said, "but I don't think it's a big red flag." Melissa Lee Phillips
mphillips@the-scientist.com Links within this article D. Steinberg, "Testing Potential Alzheimer Vaccines," The Scientist, January 21, 2002. http://www.sciencemag.org E. Russo, "The Search for Secretases," The Scientist, November 8, 1999. http://www.the-scientist.com/1999/11/08/7/1 J.B. Weitzman, "Mining myelination," The Scientist, June 27, 2002. 'http://www.the-scientist.com/article/display/20487 Robert Vassar http://www.cmb.northwestern.edu/faculty/robert_vassar.htm H. Cai et al., "BACE1 is the major beta-secretase for generation of Abeta peptides by neurons," Nature Neuroscience, March 2001. http://www.the-scientist.com/pubmed/11056475 Christian Haass http://haass.web.med.uni-muenchen.de Michael Willem http://haass.web.med.uni-muenchen.de/willem.html A.N. Garratt et al., "Neuregulin, a factor with many functions in the life of a schwann cell," Bioessays, November 2000. http://www.the-scientist.com/pubmed/11056475 Philip Wong http://www.hopkinsmedicine.org/graduateprograms/cmm/wong.html R. Vassar et al., "The beta-secretase, BACE: a prime drug target for Alzheimer's disease," Journal of Molecular Neuroscience, October 2001. http://www.the-scientist.com/pubmed/11816789
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