The N-terminal copper-binding domain of the amyloid precursor protein protects against Cu2+ neurotoxicity in vivo.
The amyloid precursor protein (APP) contains a Cu binding domain (CuBD) localized between amino acids 135 and 156 (APP135-156), which can reduce Cu2+ to Cu1+ in vitro. The physiological function of this APP domain has not yet being established; nevertheless several studies support the notion that the CuBD of APP is involved in Cu homeostasis. We used APP synthetic peptides to evaluate their protective properties against Cu2+ neurotoxicity in a bilateral intra-hippocampal injection model. We found that human APP135-156 protects against Cu2+-induced neurotoxic effects, such as, impairment of spatial memory, neuronal cell loss, and astrogliosis. APP135-156 lacking two histidine residues showed protection against Cu2+; however, APP135-156 mutated in cysteine 144, a key residue in the reduction of Cu2+ to Cu1+, did not protect against Cu2+ neurotoxicity. In accordance with recent reports, the CuBD of the Caenorhabditis elegans, APL-1, protected against Cu2+ neurotoxicity in vivo. We also found that Cu2+ neurotoxicity is associated with an increase in nitrotyrosine immunofluorescence as well as with a decrease in Cu2+ uptake. The CuBD of APP therefore may play a role in the detoxification of brain Cu.
Cerpa
Waldo F
WF
Centro FONDAP de Regulación Celular y Patología Joaquín V. Luco, MIFAB, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
Barría
María I
MI
Chacón
Marcelo A
MA
Suazo
Miriam
M
González
Mauricio
M
Opazo
Carlos
C
Bush
Ashley I
AI
Inestrosa
Nibaldo C
NC
D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000502:physiology* / Q000627:therapeutic use; D000818:Animals; D001665:Binding Sites; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry; D003300:Copper / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000633:toxicity*; D003545:Cysteine / Q000737:chemistry; D005911:Gliosis / Q000139:chemically induced / Q000517:prevention & control; D006801:Humans; D017136:Ion Transport; D008565:Membrane Proteins / Q000737:chemistry; D008568:Memory / Q000187:drug effects; D009474:Neurons / Q000166:cytology; D020258:Neurotoxicity Syndromes / Q000517:prevention & control; D010455:Peptides / Q000737:chemistry / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry; D051381:Rats; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis
C084891:APL-1 protein, C elegans; D016564:Amyloid beta-Protein Precursor; D029742:Caenorhabditis elegans Proteins; D008565:Membrane Proteins; D010455:Peptides; D011506:Proteins; C002744:3-nitrotyrosine; D014443:Tyrosine; D003300:Copper; D003545:Cysteine