Studies of copper trafficking in a mouse model of Alzheimer's disease by positron emission tomography: comparison of 64 Cu acetate and 64 CuGTSM

• Published in: Metallomics Vol. 9; no. 11; pp. 1622 - 1633
• Main Authors: Andreozzi, Erica M, Torres, Julia Baguña, Sunassee, Kavitha, Dunn, Joel, Walker-Samuel, Simon, Szanda, Istvan, Blower, Philip J
• Format: Journal Article
• Language: English
• Published: England 15-11-2017
• Subjects: Acetates - administration & dosage; Acetates - pharmacokinetics; Administration, Intravenous; Alzheimer Disease - diagnostic imaging; Alzheimer Disease - metabolism; Animals; Biological Transport; Brain - metabolism; Coordination Complexes; Copper Radioisotopes - administration & dosage; Copper Radioisotopes - pharmacokinetics; Disease Models, Animal; Humans; Metabolic Clearance Rate; Mice, Transgenic; Organometallic Compounds - administration & dosage; Organometallic Compounds - pharmacokinetics; Positron-Emission Tomography - methods; Thiosemicarbazones - administration & dosage; Thiosemicarbazones - pharmacokinetics; Tissue Distribution
• ISSN: 1756-5901; 1756-591X
• DOI: 10.1039/C7MT00227K

Alzheimer's disease can involve brain copper dyshomeostasis. We aimed to determine the effect of AD-like pathology on
Cu trafficking in mice, using positron emission tomography (PET imaging), during 24 hours after intravenous administration of ionic
Cu (Cu(ii) acetate) and
Cu-GTSM (GTSMH
= glyoxalbis(thiosemicarbazone)). Copper trafficking was evaluated in 6-8-month-old and 13-15 month-old TASTPM transgenic and wild-type mice, by imaging 0-30 min and 24-25 h after intravenous administration of
Cu tracer. Regional
Cu distribution in brains was compared by ex vivo autoradiography to that of amyloid-β plaque.
Cu-acetate showed uptake in, and excretion through, liver and kidneys. There was minimal uptake in other tissues by 30 minutes, and little further change after 24 h. Radioactivity within brain was focussed in and around the ventricles and was significantly greater in younger mice.
CuGTSM was taken up in all tissues by 30 min, remaining high in brain but clearing substantially from other tissues by 24 h. Distribution in brain was not localised to specific regions. TASTPM mice showed no major changes in global or regional
Cu brain uptake compared to wildtype after administration of
Cu acetate (unlike
Cu-GTSM) but efflux of
Cu from brain by 24 h was slightly greater in 6-8 month-old TASTPM mice than in wildtype controls. Changes in copper trafficking associated with Alzheimer's-like pathology after administration of ionic
Cu are minor compared to those observed after administration of
Cu-GTSM. PET imaging with
Cu could help understand changes in brain copper dynamics in AD and underpin new clinical diagnostic imaging methods.