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Altered copper metabolism as a theranostic biomarker in neurodegeneration

Fangyu Peng

Copper is an essential nutrient element, but excess of copper is harmful. Copper homeostasis is tightly regulated by a delicate network of copper transporters and chaperons. Wilson?s disease, or hepatolenticular degeneration, caused by mutation of ATP7B gene is characterized by accumulation of excess copper ions in liver and brain tissues. Positron emission tomography (PET) is a versatile tool for real-time assessment of copper fluxes in vivo noninvasively and quantitatively. Increased accumulation of 64Cu in liver of Atp7b-/- knockout mice, a wellestablished mouse model of Wilson?s disease, was demonstrated by measuring copper fluxes in vivo with PET/CT using copper-64 chloride (64CuCl2) as a radioactive tracer (64CuCl2-PET/CT). Age-dependent increase of 64Cu radioactivity was detected in the brain of Atp7b-/- knockout mice at 20 weeks of age compared with 64Cu radioactivity in the brains of Atp7b-/- knockout mice at 6 to 12 weeks of age. In addition to hepatolenticular degeneration, emerging body of evidence suggests the role of altered copper metabolism in pathophysiology of Alzheimer?s disease (AD) and other neurodegenerative diseases. Altered copper metabolism may be a useful theranostic biomarker for early diagnosis of AD at preclinical stage with PET/CT using 64CuCl2 as a radioactive tracer. Based on favorable outcome of copper-modulating therapy in clinical management of the patients diagnosed with Wilson?s disease, altered copper metabolism holds potential as a therapeutic target for copper modulating therapy of AD and other neurodegenerative disease associated with disturbance of cerebral copper metabolism. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder described in 1907 by Alois Alzheimer. He observed amyloid plaques and neurofibrillary tangles (NFTs) in the brain of patients showing signs of dementia. Today, AD is the most prevalent neurodegenerative disease affecting 10% of people aged 65+ and 50% of people aged 80+.