Ceruloplasmin and Neurodegeneration: A Link Between Copper Dysregulation, Iron Imbalance, and Neuronal Damage

Ceruloplasmin (Cp) is a multifunctional multicopper oxidase principally produced in the liver and, to a lesser extent, in the central nervous system. It regulates iron homeostasis and oxidative balance, Cp oxidizes ferrous iron (Fe²⁺) to ferric iron (Fe³⁺), thereby enabling its safe integration into transferrin and averting reactive oxygen species formation. Beyond its ferroxidase activity, Cp also serves as a major copper carrier in plasma and contributes to antioxidant defense mechanisms. Although, the imbalance of ceruloplasmin has been gradually recognized as a key marker in the pathogenesis of neurodegenerative disorders. It is associated with neurofibrillary tangles, amyloid plaques, tau hyperphosphorylation, oxidative stress, and mitochondrial dysfunction. In the past, Cp and neuropathology were first established when a decreased level of serum ceruloplasmin was reported as a diagnostic biomarker of Wilson's disease, a disorder characterized by copper build-up triggered by mutations in the ATP7B gene. Furthermore, some studies suggest the absence of Cp was known in aceruloplasminemia, a different neurodegenerative condition characterized by extensive deposition of iron in the brain and progressive neuronal loss. However, several studies have reported that Cp's function and expression undergo important modifications in Alzheimer's, Parkinson's, Wilson's disease, and other neurological conditions. These alterations in Cp are directly linked to disrupted metal homeostasis, alleviating oxidative stress and neuroinflammation. Thus, besides understanding the structural, metabolic, and biological roles of Cp, this review aims at explaining its possible effects on common neurological disorders. The review also focusses on the therapeutic opportunities targeting Cp-mediated pathways, primarily, focusing on how Cp dysfunction interrelates with copper metabolism, iron dysregulation, and neuroinflammatory signalling, as reported in various clinical and experimental studies. Understanding Cp mechanism may highlight novel strategies for overcoming these neurodegenerative diseases.