In vivo reduction of amyloid-beta by a mutant copper transporter.

Abstract

Cu ions have been suggested to enhance the assembly and pathogenic potential of the Alzheimer's disease amyloid-beta (Abeta) peptide. To explore this relationship in vivo, toxic-milk (txJ) mice with a mutant ATPase7b transporter favoring elevated Cu levels were analyzed in combination with the transgenic (Tg) CRND8 amyloid precursor protein mice exhibiting robust Abeta deposition. Unexpectedly, TgCRND8 mice homozygous for the recessive txJ mutation examined at 6 months of age exhibited a reduced number of amyloid plaques and diminished plasma Abeta levels. In addition, homozygosity for txJ increased survival of young TgCRND8 mice and lowered endogenous CNS Abeta at times before detectable increases in Cu in the CNS. These data suggest that the beneficial effect of the txJ mutation on CNS Abeta burden may proceed by a previously undescribed mechanism, likely involving increased clearance of peripheral pools of Abeta peptide.

• Authors: Amie L Phinney, Bettina Drisaldi, Stephen D Schmidt, Stan Lugowski, Veronica Coronado, Yan Liang, Patrick Horne, Jing Yang, Joannis Sekoulidis, Janaky Coomaraswamy, M Azhar Chishti, Diane W Cox, Paul M Mathews, Ralph A Nixon, George A Carlson, Peter St George-Hyslop, David Westaway
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 100 Issue 24 Pg. 14193-8 (Nov 25 2003) ISSN: 0027-8424 [Print] United States
• PMID: 14617772 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Cation Transport Proteins
• Copper
• Amyloid Precursor Protein Secretases
• Endopeptidases
• Aspartic Acid Endopeptidases
• Bace1 protein, mouse
• Adenosine Triphosphatases
• Copper-Transporting ATPases

Topics

• Adenosine Triphosphatases (genetics, metabolism)
• Amyloid Precursor Protein Secretases
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (metabolism)
• Animals
• Aspartic Acid Endopeptidases
• Brain (metabolism)
• Cation Transport Proteins (genetics, metabolism)
• Copper (metabolism)
• Copper-Transporting ATPases
• Endopeptidases (metabolism)
• Female
• Male
• Mice
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Mice, Transgenic
• Phenotype
• Protein Processing, Post-Translational