In vivo reduction of amyloid-β by a mutant copper transporter

Abstract

Cu ions have been suggested to enhance the assembly and pathogenic potential of the Alzheimer's disease amyloid-␤ (A␤) peptide. To explore this relationship in vivo, toxic-milk (tx J ) 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 A␤ deposition. Unexpectedly, TgCRND8 mice homozygous for the recessive tx J mutation examined at 6 months of age exhibited a reduced number of amyloid plaques and diminished plasma A␤ levels. In addition, homozygosity for tx J increased survival of young TgCRND8 mice and lowered endogenous CNS A␤ at times before detectable increases in Cu in the CNS. These data suggest that the beneficial effect of the tx J mutation on CNS A␤ burden may proceed by a previously undescribed mechanism, likely involving increased clearance of peripheral pools of A␤ peptide. A lzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by extracellular deposition of amyloid-␤ (A␤) as senile plaques and intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles (1). A␤ is generated by secretase-mediated endoproteolysis of the amyloid precursor protein (APP), and familial AD mutations skew APP processing to favor production of pro-amyloidogenic forms of the peptide or net A␤ production and thus drive disease pathogenesis. Although there is growing interest in defining pathogenic subvarieties of A␤ [e.g., secreted oligomeric assemblies such as A␤-derived diffusible ligands (2) and intracellular forms (3)], modulators of APP and A␤ biology in sporadic disease have remained more elusive. One area of particular interest concerns the role of transition metals.Cu and Zn ions are abundant in the normal brain (4-6), and direct measurements of metal levels have indicated altered homeostasis in AD (7-10). Interestingly, APP has a selective, high-affinity Cu-binding site in the extracellular (ecto-) domain that is capable of reducing Cu(II) to Cu(I) (11), and a recent structural analysis of this domain has revealed some similarity to previously identified Cu chaperone proteins (12). In addition to the ectodomain Cu-binding site of APP, A␤ peptide also contains binding sites for . A␤-metal interaction may drive both fibril formation and free radical production (13,(16)(17)(18), findings potentially relevant to AD pathogenesis in vivo, given that metal chelators can resolubilize A␤ aggregates from postmortem AD brain (19). On the other hand, studies of APP processing in cultured cells have revealed stimulation of the ␣-secretase pathway for APP processing by extracellular Cu ions (20). As this pathway cleaves the A␤ domain of APP into two fragments, it has a potential to be anti-amyloidogenic. Prompted by these divergent observations, we devised a genetic experiment to investigate how Cu might modulate A␤-dependent pathologies in vivo by using the transgenic (Tg) CRND8 line of TgAPP mice (21,22) in conjunction with a mutant allele of the CuATPase7b c...

Copper brain homeostasis: Role of amyloid precursor protein and prion protein

“…The above in vivo evidence strongly suggests a beneficial effect for Cu in different AD models (18,19), indicating that Cu could be a positive player in stopping the progress of AD.…”

“…Finally, they stated that their 'observation should be regarded as a proof-of-concept for a prophylactic approach to address a nervous system copper deficiency in AD'. Phinney et al (2003) (19) showed that copper levels in brains of APP-overexpressing transgenic TgCRND8 mice were lower than in non-Tg controls, even though the Tg mice exhibit a substantial burden of dense-cored plaques and high Ab levels. Moreover, Ab species were lower in tx J/J mice (mutant of the ATPase7b copper transporter favoring elevated copper levels) than in age-matched controls.…”

Small molecule inhibitors of Aβ‐aggregation and neurotoxicity

“…Cu 21 decreased Ab deposits in APP23 transgenic mice [Bayer et al, 2003] and Ab levels were reduced by a mutant Cu 21 transporter [Phinney et al, 2003]. Additionally, overexpression of human Ab peptides in transgenic mice decreased brain Cu 21 [Maynard et al, 2002].…”

Magnesium in the Central Nervous System

“…Furthermore, SP stimulates immune cells to release pro--inflammatory cytokines, including TNF--α and several interleukin family members (IL--1β, 1L--2 and Il--6) resulting in further inflammation (Delgado et al, 2003). Additionally, NK--1R activation stimulates second messenger pathways that increase Ca 2+ entry to neurons (Suh and Hille, 2005;Yang et al, 2003). Since SP also activates NMDAR (Wu et al, 2004), Ca 2+ influx through these channels may lead to excitotoxicity and the production of free radicals such as peroxynitrite, which can be highly toxic to cellular macromolecules.…”

“…Disturbed homeostasis of these biometals in the AD brain (decreased copper levels, and increased concen--trations of iron, zinc, and manganese) has been reported (Cornett et al, 1998;Deibel et al, 1996). An imbalance of zinc and copper has been shown to significantly alter APP processing and Aβ generation in relevant animal models (Bayer et al, 2003;Borchardt et al, 1999;Phinney et al, 2003;Sparks and Schreurs, 2003;Lee et al, 2002;Friedlich et al, 2004).…”