Genetic deletion of BACE1 in mice affects remyelination of sciatic nerves.
BACE1 is a promising therapeutic and preventive target for Alzheimer's disease because it is essential for amyloid deposition. However, the recent demonstration of BACE1 in modulating developmental myelination in both peripheral and central nervous systems raises a concern of its effect on myelin maintenance or remyelination, and inhibition of these processes will potentially be detrimental to the BACE1 inhibitor users who are susceptible to myelination diseases such as adult peripheral nerve injury or multiple sclerosis. In this report, we investigated the role of BACE1 during peripheral nerve remyelination in wild-type (WT) and BACE1-null mice. We show here that genetic deletion of BACE1 affects sciatic nerve remyelination. The impaired remyelination appears to stem from the loss of neuregulin-1 cleavage by BACE1. To demonstrate a direct cleavage of neuregulin-1 by BACE1, we have identified a BACE1 cleavage site that turns out be highly conserved among neuregulin-1 paralogues. Moreover, we show that neuregulin-1 family member neuregulin-3 is also cleavable by BACE1. We hypothesize that the BACE1-cleaved extracellular domain of axonal neuregulin-1, perhaps neuregulin-3 as well, binds to Schwann cell ErbB receptors, which in turn regulate remyelination. Pharmacological inhibition of BACE1 should be carefully monitored to avoid alteration of signaling pathway that regulates remyelination.
Hu
Xiangyou
X
Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USA.
He
Wanxia
W
Diaconu
Claudiu
C
Tang
Xiaoying
X
Kidd
Grahame J
GJ
Macklin
Wendy B
WB
Trapp
Bruce D
BD
Yan
Riqiang
R
D000544:Alzheimer Disease / Q000628:therapy; D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D001665:Binding Sites; D002460:Cell Line; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology; D009416:Nerve Regeneration / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism; D020890:Neuregulin-1; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012584:Sciatic Nerve / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D011994:Recombinant Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse