In vivo Reduction of Amyloid-β by a Mutant Copper Transporter

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 24; pp. 14193 - 14198
• Main Authors: Phinney, Amie L., Drisaldi, Bettina, Schmidt, Stephen D., Lugowski, Stan, Coronado, Veronica, Liang, Yan, Horne, Patrick, Yang, Jing, Sekoulidis, Joannis, Coomaraswamy, Janaky, Chishti, M. Azhar, Cox, Diane W., Mathews, Paul M., Nixon, Ralph A., Carlson, George A., St George-Hyslop, Peter, Westaway, David
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25-11-2003; National Acad Sciences
• Subjects: Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Alzheimer's disease; Alzheimers disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases; Amyloids; Animals; Antibodies; Aspartic Acid Endopeptidases; Biological Sciences; Brain - metabolism; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Central nervous system; Copper; Copper - metabolism; Copper-transporting ATPases; Endopeptidases - metabolism; Female; Genetic mutation; Genotypes; Homozygotes; Ions; Male; Medical research; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Mutant Strains; Mice, Transgenic; Mutation; Phenotype; Protein Processing, Post-Translational; T tests
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2332851100

Cu ions have been suggested to enhance the assembly and pathogenic potential of the Alzheimer's disease$amyloid\!-\!\beta\>(A\beta)$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 Aβ deposition. Unexpectedly, TgCRND8 mice homozygous for the recessive txJmutation examined at 6 months of age exhibited a reduced number of amyloid plaques and diminished plasma Aβ levels. In addition, homozygosity for txJincreased survival of young TgCRND8 mice and lowered endogenous CNS Aβ at times before detectable increases in Cu in the CNS. These data suggest that the beneficial effect of the txJmutation on CNS Aβ burden may proceed by a previously undescribed mechanism, likely involving increased clearance of peripheral pools of Aβ peptide.