Copper homeostasis and cuproptosis in Alzheimer's disease (Review)

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neuroinflammation, synaptic dysfunction and neuronal loss. Research has revealed a connection between copper metabolism and the pathophysiology of AD, particularly through a newly identified form of copper‑dependent cell death referred to as cuproptosis. Cuproptosis is driven by the aggregation of lipoylated proteins and proteotoxic stress caused by excessive copper accumulation, leading to cellular demise, which is a key event in AD. While studies on copper levels in the brain in AD remain inconclusive, there is mounting evidence suggesting that an imbalance in copper homeostasis, particularly elevated labile copper levels, contributes to oxidative damage and neurodegeneration in patients with AD. The present review examines the role of cuproptosis in AD and discusses how targeting this pathway may provide novel therapeutic opportunities. By investigating the underlying mechanisms and potential clinical implications, the present review highlights that regulation of cuproptosis provides a promising approach for modulating disease progression and developing personalized treatment strategies for AD.

Keywords: Alzheimer's disease; cuproptosis; neuroinflammation.

Figure 1

Copper absorption and transport. Dietary copper is primarily absorbed in the duodenum and proximal small intestine via the CTR1 transporter, following reduction of Cu²⁺ to Cu⁺ by STEAP and DCYTB. Once absorbed, copper is either stored in intestinal cells by metallothioneins or transported to the liver via ATP7A. In the liver, copper is distributed and stored, with any excess excreted through bile. This process ensures systemic copper homeostasis and bioavailability. CP, ceruloplasmin; CTR1, copper transporter 1; DCYTB, duodenal cytochrome B; HIS, histidine; HSA, human serum albumin; MG, metal group; MT, metallothionein; STEAP, six-transmembrane epithelial antigen of the prostate.

Figure 2

Mechanism of cuproptosis in neurons. Excessive copper [Cu²⁺] is transported into cells via elesclomol. The accumulation of Cu²⁺ disrupts Fe-S cluster proteins and lipoic acid-dependent enzymes such as DLAT. Copper-induced stress depletes GSH, an antioxidant that protects cells from oxidative damage. Additionally, some extracellular Cu²⁺ is reduced to Cu⁺ by metalloreductases and transported into cells via CTR1. This Cu⁺ in mitochondria can directly trigger cuproptosis. Cu⁺/Cu²⁺, reduced/oxidized copper ion; CTR1, copper transporter 1; DLAT, dihydrolipoamide S-acetyltransferase; FDX1, ferredoxin 1; Fe-S, iron-sulfur; GSH, glutathione; LA, lipoic acid; LIAS, lipoic acid synthase; MT, metallothionein.

Figure 3

Copper dyshomeostasis and its dual impact on AD. Both copper excess and deficiency contribute to AD pathogenesis. Copper overload induces Aβ aggregation, Tau phosphorylation, oxidative stress (via the Fenton reaction) and neuroinflammation with neuronal loss. Conversely, copper deficiency reduces antioxidant enzymes (such as SOD, CP and LOX) and Cox activity, leading to impaired mitochondrial function and elevated ROS levels. These disruptions in copper homeostasis accelerate neurodegeneration. Aβ, amyloid-β; AD, Alzheimer's disease; CP, ceruloplasmin; Cox, cyclooxygenase; CTR1, copper transporter 1; DLAT, dihydrolipoamide S-acetyltransferase; Fe-S, iron-sulfur; LOX, lysyl oxidase; ROS, reactive oxygen species; SOD, superoxide dismutase; STEAP, six-transmembrane epithelial antigen of the prostate.