title: BACE1 regulates the proliferation and cellular functions of Schwann cells.
abstract: BACE1 is an indispensable enzyme for generating β-amyloid peptides, which are excessively accumulated in brains of Alzheimer's patients. However, BACE1 is also required for proper myelination of peripheral nerves, as BACE1-null mice display hypomyelination. To determine the precise effects of BACE1 on myelination, here we have uncovered a role of BACE1 in the control of Schwann cell proliferation during development. We demonstrate that BACE1 regulates the cleavage of Jagged-1 and Delta-1, two membrane-bound ligands of Notch. BACE1 deficiency induces elevated Jag-Notch signaling activity, which in turn facilitates proliferation of Schwann cells. This increase in proliferation leads to shortened internodes and decreased Schmidt-Lanterman incisures. Functionally, evoked compound action potentials in BACE1-null nerves were significantly smaller and slower, with a clear decrease in excitability. BACE1-null nerves failed to effectively use lactate as an alternative energy source under conditions of increased physiological activity. Correlatively, BACE1-null mice showed reduced performance on rotarod tests. Collectively, our data suggest that BACE1 deficiency enhances proliferation of Schwann cell due to the elevated Jag1/Delta1-Notch signaling, but fails to myelinate axons efficiently due to impaired the neuregulin1-ErbB signaling, which has been documented.
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195.|Department of Anatomy, Anhui Medical University, Hefei, 230032, Anhui, People's Republic of China.
authors.forename: Xiangyou
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195.
authors.forename: Hailong
authors.initials: H
authors.lastname: Hou
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195.
authors.forename: Chinthasagar
authors.initials: C
authors.lastname: Bastian
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195.
authors.forename: Wanxia
authors.initials: W
authors.lastname: He
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195.
authors.forename: Shupeng
authors.initials: S
authors.lastname: Qiu
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Yin
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195.
authors.forename: Grahame J
authors.initials: GJ
authors.lastname: Kidd
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Brunet
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Trapp
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195.
authors.forename: Selva
authors.initials: S
authors.lastname: Baltan
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195.
authors.forename: Riqiang
authors.identifier: 0000-0001-7195-7617
authors.initials: R
authors.lastname: Yan
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001369:Axons / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology*; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism*; D012584:Sciatic Nerve / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: Alzheimer's β-secretase; BACE1; Jagged; Notch; Schmidt-Lanterman clefts; myelin sheath; myelination; node of Ranvier