Axonal and Schwann cell BACE1 is equally required for remyelination of peripheral nerves.
Inhibition of β-site APP cleaving enzyme 1 (BACE1) is being pursued as a therapeutic target for treating patients with Alzheimer's disease because BACE1 is the sole β-secretase for generating β-amyloid peptide. Knowledge regarding the other cellular functions of BACE1 is therefore critical for the safe use of BACE1 inhibitors in human patients. BACE1 deficiency in mice causes hypomyelination during development and impairs remyelination in injured sciatic nerves. Since BACE1 is expected to be ubiquitously expressed, we asked whether axonal or Schwann cell BACE1 is required for optimal remyelination. By swapping sciatic nerve segments from BACE1-null mice with the corresponding wild-type nerve segments or vice versa, we tested how a deficiency of BACE1 in Schwann cells or axons affects remyelination. Our results show that BACE1 in axons and Schwann cells is similarly important for remyelination of regenerated axons. Nerve injury induces BACE1 transcription and protein levels are elevated in Schwann cells. Expression of type I neuregulin 1 (Nrg1), rather than type III Nrg1, was induced by Schwann cells, and the abolished Nrg1 cleavage in BACE1-null Schwann cells contributed to decreased remyelination of regenerated axons. Hence, this study is the first to demonstrate the equal importance of axonal and Schwann cell BACE1 for remyelination of injured nerves.
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, and Department of Anatomy, Anhui Medical University, Hefei 230032, Anhui, People's Republic of China.
Xiangyou
X
Hu
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, and.
Jinxuan
J
Hu
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, and.
Lu
L
Dai
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, and.
Bruce
B
Trapp
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, and yanr@ccf.org.
Riqiang
R
Yan
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000502:physiology*; D001369:Axons / Q000201:enzymology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000235:genetics / Q000502:physiology*; D009416:Nerve Regeneration / Q000235:genetics / Q000502:physiology*; D009417:Nerve Tissue / Q000637:transplantation; D020890:Neuregulin-1 / Q000096:biosynthesis / Q000235:genetics; D010525:Peripheral Nerves / Q000502:physiology*; D012583:Schwann Cells / Q000201:enzymology / Q000502:physiology*; D012584:Sciatic Nerve / Q000502:physiology / Q000637:transplantation
D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
BACE1; cell autonomy; neuregulin; remyelination; sciatic nerve transplantation; secretase