title: Reduced BACE1 activity enhances clearance of myelin debris and regeneration of axons in the injured peripheral nervous system.
abstract: β-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is an aspartyl protease best known for its role in generating the amyloid-β peptides that are present in plaques of Alzheimer's disease. BACE1 has been an attractive target for drug development. In cultured embryonic neurons, BACE1-cleaved N-terminal APP is further processed to generate a fragment that can trigger axonal degeneration, suggesting a vital role for BACE1 in axonal health. In addition, BACE1 cleaves neuregulin 1 type III, a protein critical for myelination of peripheral axons by Schwann cells during development. Here, we asked whether axonal degeneration or axonal regeneration in adult nerves might be affected by inhibition or elimination of BACE1. We report that BACE1 knock-out and wild-type nerves degenerated at a similar rate after axotomy and to a similar extent in the experimental neuropathies produced by administration of paclitaxel and acrylamide. These data indicate N-APP is not the sole culprit in axonal degeneration in adult nerves. Unexpectedly, however, we observed that BACE1 knock-out mice had markedly enhanced clearance of axonal and myelin debris from degenerated fibers, accelerated axonal regeneration, and earlier reinnervation of neuromuscular junctions, compared with littermate controls. These observations were reproduced in part by pharmacological inhibition of BACE1. These data suggest BACE1 inhibition as a therapeutic approach to accelerate regeneration and recovery after peripheral nerve damage.
authors.affiliation: Departments of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Farah
authors.forename: Bao Han
authors.initials: BH
authors.lastname: Pan
authors.forename: Paul N
authors.initials: PN
authors.lastname: Hoffman
authors.forename: Dana
authors.initials: D
authors.lastname: Ferraris
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Thien
authors.initials: T
authors.lastname: Nguyen
authors.forename: Philip C
authors.initials: PC
authors.lastname: Wong
authors.forename: Donald L
authors.initials: DL
authors.lastname: Price
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.forename: John W
authors.initials: JW
authors.lastname: Griffin
mesh_terms: D020106:Acrylamide / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D001369:Axons / Q000502:physiology* / Q000648:ultrastructure; D001710:Biotin / Q000031:analogs & derivatives / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000502:physiology / Q000637:transplantation; D007150:Immunohistochemistry; D015918:Infusion Pumps, Implantable; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009186:Myelin Sheath / Q000378:metabolism*; D009410:Nerve Degeneration / Q000473:pathology; D009416:Nerve Regeneration / Q000502:physiology*; D009469:Neuromuscular Junction / Q000502:physiology; D017239:Paclitaxel / Q000494:pharmacology; D017933:Peripheral Nervous System / Q000502:physiology*; D010587:Phagocytosis / Q000502:physiology; D012584:Sciatic Nerve / Q000293:injuries / Q000637:transplantation; D014855:Wallerian Degeneration / Q000473:pathology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; C070614:neurobiotin; D020106:Acrylamide; D001710:Biotin; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D017239:Paclitaxel