In vivo reduction of amyloid-beta by a mutant copper transporter.
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.
Phinney
Amie L
AL
Center for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada M5S 3H2.
Drisaldi
Bettina
B
Schmidt
Stephen D
SD
Lugowski
Stan
S
Coronado
Veronica
V
Liang
Yan
Y
Horne
Patrick
P
Yang
Jing
J
Sekoulidis
Joannis
J
Coomaraswamy
Janaky
J
Chishti
M Azhar
MA
Cox
Diane W
DW
Mathews
Paul M
PM
Nixon
Ralph A
RA
Carlson
George A
GA
St George-Hyslop
Peter
P
Westaway
David
D
D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D010450:Endopeptidases / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D010641:Phenotype; D011499:Protein Processing, Post-Translational
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D027682:Cation Transport Proteins; D003300:Copper; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases