Chelation and intercalation: complementary properties in a compound for the treatment of Alzheimer's disease.
Selective application of metal chelators to homogenates of human Alzheimer's disease (AD) brain has led us to propose that the architecture of aggregated beta-amyloid peptide, whether in the form of plaques or soluble oligomers, is determined at least in part by high-affinity binding of transition metals, especially copper and zinc. Of the two metals, copper is implicated in reactive oxygen species generating reactions, while zinc appears to be associated with conformational and antioxidant activity. We tested the copper chelators trientine, penicillamine, and bathophenanthroline for their ability to mobilize brain Abeta as measured against our benchmark compound bathocuproine (BC). All of these agents were effective in solubilizing brain Abeta, although BC was the most consistent across the range of AD brain tissue samples tested. Similarly, all of the copper chelators depleted copper in the high-speed supernatants. BC alone had no significant effect upon zinc levels in the soluble fraction. BC extraction of brain tissue from C100 transgenic mice (which express human Abeta but do not develop amyloid) revealed SDS-resistant dimers as Abeta was mobilized from the sedimentable to the soluble fraction. NMR analysis showed that, in addition to its copper chelating properties, BC interacts with Abeta to form a complex independent of the presence of copper. Such hybrid copper chelating and "chain breaking" properties may form the basis of a rational design for a therapy for Alzheimer's disease.
The Department of Pathology, The University of Melbourne, Melbourne, Victoria, 3010, Australia.
R A
RA
Cherny
K J
KJ
Barnham
T
T
Lynch
I
I
Volitakis
Q X
QX
Li
C A
CA
McLean
G
G
Multhaup
K
K
Beyreuther
R E
RE
Tanzi
C L
CL
Masters
A I
AI
Bush
D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D019906:Nuclear Magnetic Resonance, Biomolecular; D010396:Penicillamine / Q000378:metabolism / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D010618:Phenanthrolines / Q000378:metabolism / Q000494:pharmacology; D010865:Pilot Projects; D012995:Solubility; D014266:Trientine / Q000378:metabolism / Q000494:pharmacology; D015032:Zinc / Q000737:chemistry
D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D010455:Peptides; D010618:Phenanthrolines; C006686:bathophenanthroline; C028559:bathocuproine sulfonate; D003300:Copper; D010396:Penicillamine; D015032:Zinc; D014266:Trientine