The purpose of this proposal is to determine feasibility and use of altered copper metabolism as a new theranostic biomarker for early diagnosis and treatment of Alzheimer's disease (AD). Copper is an essential nutrient element in mammals, but excess of copper is cytotoxic. Copper homeostasis is tightly regulated by a delicate network of copper transporters and chaperons. Mutation of ATP7B gene causes Wilson's disease, an inherited copper metabolism disorder characterized by hepatic and neurological symptoms due to harmful effect of excess copper accumulation in live and brain. Emerging body of evidence suggests role of altered copper metabolism in pathogenesis of AD. However, little is known about real-time copper metabolism in human brains due to lack of a tool for real-time assessment of copper fluxes in vivo. Positron emission tomography (PET) is a versatile tool for real-time assessment of copper fluxes in live organism. Increased accumulation of 64C was demonstrated in liver of Atp7b -/- knockout mice, a mouse model of Wilson's disease, by PET/CT using 64CuCl2 as a radiotracer. We assessed copper metabolism in brain of Tau transgenic mouse model of AD and discovered that 64Cu radioactivity in brain tissues of Tau Tau- P301L mutant transgenic mice was significantly higher than 64Cu radioactivity in brain tissue of normal control mice. The data of our preliminary experiments suggested potentials of altered copper accumulation as a new biomarker for early diagnosis of AD by PET/CT. Additionally, altered copper metabolism holds potential as a therapeutic target for early treatment of AD with copper modulating therapy. Herein, we propose longitudinal assessment of age-dependent change of copper metabolism in brain of Tau-P301L mutant transgenic mice by PET/CT using 64CuCl2 as a radiotracer (64CuCl2-PET/CT). In addition, we will explore potential of altered copper metabolism as a therapeutic target for copper modulating therapy in Tau-P301L mutant transgenic mice.
Our specific aims of this proposal are:
Aim 1. To determine the feasibility of altered copper metabolism as a new biomarker for early diagnosis of AD based on longitudinal assessment of age-dependent change of 64Cu radioactivity in brain of Tau-P301L mutant transgenic mice using 64CuCl2 -PET/CT.
Aim 2 : To explore the therapeutic potentials of copper-modulating therapy in AD by monitoring effects of clioquinol on altered copper metabolism and improvement of Tauopathological changes in Tau-P301L mutant transgenic mice by microPET/CT using 64CuCl2 as a radiotracer and histolochemical analysis of NFT burden in mouse brain tissues. Outcome of this study may shed new light on the role of altered copper metabolism in pathogenesis of AD related to Taupathology, determine feasibility of using 64CuCl2-PET/CT for early diagnosis of AD, and provide evidence to support further study of altered copper metabolism as a therapeutic target for early treatment of AD by copper modulating therapy. Furthermore, altered copper metabolism holds potentials as a surrogate biomarker for monitoring therapeutic effects of other anti-AD drugs targeting tauopathies by PET/CT using 64CuCl2 as a radiotracer.
This project aims to explore altered copper metabolism as a novel theranostic biomarker for early diagnosis and treatment of Alzheimer's disease. This new theranostic biomarker may be used for early diagnosis of Alzheimer's disease with PET/CT using positron emitting copper-64 chloride as a radiotracer. Altered copper metabolism also holds potential as a therapeutic target for treatment of Alzheimer's disease.
|Power, Melinda C; Mormino, Elizabeth; Soldan, Anja et al. (2018) Combined neuropathological pathways account for age-related risk of dementia. Ann Neurol 84:10-22|
|Peng, Fangyu; Xie, Fang; Muzik, Otto (2018) Alteration of Copper Fluxes in Brain Aging: A Longitudinal Study in Rodent Using 64CuCl2-PET/CT. Aging Dis 9:109-118|
|Xie, Fang; Xi, Yin; Pascual, Juan M et al. (2017) Age-dependent changes of cerebral copper metabolism in Atp7b -/- knockout mouse model of Wilson's disease by [64Cu]CuCl2-PET/CT. Metab Brain Dis 32:717-726|
|Xie, Fang; Peng, Fangyu (2017) Radiopharmaceuticals for Assessment of Altered Metabolism and Biometal Fluxes in Brain Aging and Alzheimer's Disease with Positron Emission Tomography. J Alzheimers Dis 59:527-536|
|Peng, Fangyu; Muzik, Otto; Gatson, Joshua et al. (2015) Assessment of Traumatic Brain Injury by Increased 64Cu Uptake on 64CuCl2 PET/CT. J Nucl Med 56:1252-7|