Pharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice

Sci Rep. 2016 Feb 25;6:21917. doi: 10.1038/srep21917.

Abstract

Melanocytes of the hair follicle produce melanin and are essential in determining the differences in hair color. Pigment cell-specific MELanocyte Protein (PMEL17) plays a crucial role in melanogenesis. One of the critical steps is the amyloid-like functional oligomerization of PMEL17. Beta Site APP Cleaving Enzyme-2 (BACE2) and γ-secretase have been shown to be key players in generating the proteolytic fragments of PMEL17. The β-secretase (BACE1) is responsible for the generation of amyloid-β (Aβ) fragments in the brain and is therefore proposed as a therapeutic target for Alzheimer's disease (AD). Currently BACE1 inhibitors, most of which lack selectivity over BACE2, have demonstrated efficacious reduction of amyloid-β peptides in animals and the CSF of humans. BACE2 knock-out mice have a deficiency in PMEL17 proteolytic processing leading to impaired melanin storage and hair depigmentation. Here, we confirm BACE2-mediated inhibition of PMEL17 proteolytic processing in vitro in mouse and human melanocytes. Furthermore, we show that wildtype as well as bace2(+/-) and bace2(-/-) mice treated with a potent dual BACE1/BACE2 inhibitor NB-360 display dose-dependent appearance of irreversibly depigmented hair. Retinal pigmented epithelium showed no morphological changes. Our data demonstrates that BACE2 as well as additional BACE1 inhibition affects melanosome maturation and induces hair depigmentation in mice.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / metabolism*
  • Blotting, Western
  • Cell Line, Tumor
  • Female
  • Hair / drug effects
  • Hair / metabolism*
  • Hair / pathology
  • Humans
  • Male
  • Melanins / metabolism
  • Melanocytes / cytology
  • Melanocytes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Fluorescence
  • Peptide Fragments / metabolism
  • Picolinic Acids / pharmacology
  • Pigmentation / drug effects
  • Prosencephalon / metabolism
  • Prosencephalon / pathology
  • Protease Inhibitors / pharmacology
  • RNA, Messenger / metabolism
  • Real-Time Polymerase Chain Reaction
  • Thiazines / pharmacology
  • Uvea / drug effects
  • Uvea / metabolism
  • Uvea / pathology
  • gp100 Melanoma Antigen / antagonists & inhibitors
  • gp100 Melanoma Antigen / metabolism*

Substances

  • Amyloid beta-Peptides
  • Bace2 protein, mouse
  • Melanins
  • NB-360
  • Peptide Fragments
  • Picolinic Acids
  • Pmel protein, mouse
  • Protease Inhibitors
  • RNA, Messenger
  • Thiazines
  • amyloid beta-protein (1-40)
  • gp100 Melanoma Antigen
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse