Copper Imbalance in Alzheimer’s Disease: Meta-Analysis of Serum, Plasma, and Brain Specimens, and Replication Study Evaluating ATP7B Gene Variants

Abstract

Evidence indicates that patients with Alzheimer’s dementia (AD) show signs of copper (Cu) dyshomeostasis. This study aimed at evaluating the potential of Cu dysregulation as an AD susceptibility factor. We performed a meta-analysis of 56 studies investigating Cu biomarkers in brain specimens (pooled total of 182 AD and 166 healthy controls, HC) and in serum/plasma (pooled total of 2929 AD and 3547 HC). We also completed a replication study of serum Cu biomarkers in 97 AD patients and 70 HC screened for rs732774 and rs1061472 ATP7B, the gene encoding for the Cu transporter ATPase7B. Our meta-analysis showed decreased Cu in AD brain specimens, increased Cu and nonbound ceruloplasmin (Non-Cp) Cu in serum/plasma samples, and unchanged ceruloplasmin. Serum/plasma Cu excess was associated with a three to fourfold increase in the risk of having AD. Our replication study confirmed meta-analysis results and showed that carriers of the ATP7B AG haplotype were significantly more frequent in the AD group. Overall, our study shows that AD patients fail to maintain a Cu metabolic balance and reveals the presence of a percentage of AD patients carrying ATP7B AG haplotype and presenting Non-Cp Cu excess, which suggest that a subset of AD subjects is prone to Cu imbalance. This AD subtype can be the target of precision medicine-based strategies tackling Cu dysregulation.

Regulatory miRNAs in Cardiovascular and Alzheimer’s Disease: A Focus on Copper

“…When not bound to proteins or enzymes, Fe and Cu undergo redox cycling reactions with H 2 O 2 (Fenton-type reactions), resulting in the production of ROS, of which H 2 O 2 can diffuse through the cell membrane and then produce the very reactive hydroxyl radical (HO•) catalyzed by Cu and Fe (Fenton-type reactions) [ 10 ], eventually leading to tissue damage. The picture of Cu imbalance in AD emerging from a recent meta-analysis [ 11 ] is consistent with a shift or displacement of the metal from functional bound Cu to a labile toxic non-ceruloplasmin Cu pool that can easily cross the blood–brain barrier, affecting the aggregation of Aβ and likely producing oxidative stress [ 1 , 9 ].…”

“…Cu imbalance has been linked to AD risk and pathogenesis [ 1 , 11 , 102 ]. The effects of Cu toxicity are thought to be associated with abnormal energy metabolism, an increase in glycolysis, and mitochondrial oxidative and DNA damage, as recently structured in a disease hypothesis construct [ 103 ].…”

“…In 2013, Singh resumed Sparks Schrewer’s seminal studies on AD and demonstrated that excess non-ceruloplasmin Cu is toxic [ 104 ]. (Readers are referred to specialized articles for the non-ceruloplasmin Cu role in AD [ 1 , 11 ].) In that study, Singh and collaborators (2013) showed that 0.13 mg/day of Cu in drinking water for 90 days induced Cu accumulation in the brain capillaries of aging mice and reduced the levels of low-density lipoprotein receptor-related protein 1 (LRP1).…”

“…Several studies have revealed how specific miRNAs are regulated by HIF during hypoxic conditions, thus establishing a link between HIF, miRNA, and CVD states [ 25 ]. In the same line of thinking, since HIF is strictly linked to Cu regulation, HIF can be proposed as the possible missing link between Cu and miRNA regulation in AD, which is known to be associated with Cu imbalance [ 11 ] and cardiovascular risk.…”

Is There a Connection between the Metabolism of Copper, Sulfur, and Molybdenum in Alzheimer’s Disease? New Insights on Disease Etiology

“…NCp–Cu characterizes AD patients, and possible genetic defects of the ATP7B gene, which encodes for a P-type ATPase protein involved in the Cu transport, were identified in AD patients [ 48 ]. In AD, Cu decreases in the brain but increases in the serum due to the nCp–Cu component increase [ 36 , 49 ]. Excess Cu speeds up some early AD events, such as the induction of aggregation of Aβ peptides via enhancing the amyloidogenic cleavage of amyloid precursor protein (APP) and the hyperphosphorylation of Tau by stimulating GSK3β kinase, disturbing brain function of wild-type mice and exacerbating neurodegenerative changes in a mouse model of AD [ 50 ].…”