An enzyme that helps generate clumps of amyloid-β in the brains of people with Alzheimer disease also has a role in myelinating axons, according to a study in Science (doi: 10.1126/science.1132341). The findings sound a cautionary note for ongoing efforts to develop drugs to inactivate this enzyme.
The enzyme, BACE1 (beta-site amyloid precursor protein–cleaving enzyme 1), is required to cleave amyloid-β from a larger precursor. (After BACE1-mediated cleavage, the presenilin-containing complex γ-secretase makes the final cleavage, liberating amyloid-β.)
Michael Willem et al. found that BACE1 seems to be required for processing a signal, the EGF-like factor neuregulin 1,that activates receptors on Schwann cells. Activation of these receptors is required for myelination.
One observation supporting this hypothesis was that animals deficient in BACE-1 had myelin defects in the peripheral nerves. Shown is a cross-section of the sciatic nerve of an 8-day-old BACE1-deficient mouse; myelin sheath in black. The myelin is thinner than in wild-type mice and some axons lack myelin altogether.
Peripheral nerve myelination occurs early in life, so it is unclear how BACE1 inhibition might affect older animals. Whether BACE1 also has a role in myelination of the central nervous system is also unclear.
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Schubert, C. Alzheimer disease: BACE1 branches out. Nat Med 12, 1123 (2006). https://doi.org/10.1038/nm1006-1123
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DOI: https://doi.org/10.1038/nm1006-1123
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