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Bagheri, S. Reasons for Neuron Copper Deficiency in Alzheimer Patients. Encyclopedia. Available online: https://encyclopedia.pub/entry/18228 (accessed on 11 February 2026).
Bagheri S. Reasons for Neuron Copper Deficiency in Alzheimer Patients. Encyclopedia. Available at: https://encyclopedia.pub/entry/18228. Accessed February 11, 2026.
Bagheri, Soghra. "Reasons for Neuron Copper Deficiency in Alzheimer Patients" Encyclopedia, https://encyclopedia.pub/entry/18228 (accessed February 11, 2026).
Bagheri, S. (2022, January 14). Reasons for Neuron Copper Deficiency in Alzheimer Patients. In Encyclopedia. https://encyclopedia.pub/entry/18228
Bagheri, Soghra. "Reasons for Neuron Copper Deficiency in Alzheimer Patients." Encyclopedia. Web. 14 January, 2022.
Reasons for Neuron Copper Deficiency in Alzheimer Patients
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This entry is adapted from the peer-reviewed paper 10.3390/inorganics10010006

Alzheimer’s disease is a progressive neurodegenerative disorder that eventually leads the affected patients to die. The appearance of senile plaques in the brains of Alzheimer’s patients is known as a main symptom of this disease. The plaques consist of different components, and according to numerous reports, their main components include beta-amyloid peptide and transition metals such as copper. In this disease, metal dyshomeostasis leads the number of copper ions to simultaneously increase in the plaques and decrease in neurons. Copper ions are essential for proper brain functioning, and one of the possible mechanisms of neuronal death in Alzheimer’s disease is the copper depletion of neurons. However, the reason for the copper depletion is as yet unknown.

beta-amyloid peptide microglia copper deficiency inflammatory cytokines NMDA receptor

1. Introduction

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder related to aging [1]. The number of Alzheimer’s patients in 2019 was estimated to be 50 million, and that figure is expected to exceed 152 million by 2050. It was approximated that about US$1 trillion was spent on AD in 2019 [2]. Despite the deadly nature of this disease and its high prevalence as well as the consequent economic burden, after more than a hundred years have passed since its discovery, no effective treatment has been found up to now. The complexity of the disease means its recognition and treatment development have been similar to the story of the “elephant in the dark”, with various researchers attributing various causes to the disease as well as studying wide-ranging and overlapping options for treatment of different aspects of the condition.
There are several hypotheses concerning the cause of AD based on the available experimental data [3]. Yet, the main accredited hypothesis of the ‘amyloid cascade’ has been challenged in the last decade [4]. Metal dyshomeostasis is among the relatively new proposed mechanisms for AD onset [5][6][7]. Considering that Aβ is produced in the brain under physiological conditions (as a soluble component), the “metal hypothesis” has also been put forward, in which Aβ binding to metal ions, especially copper and zinc ions, causes pathogenic Aβ deposits to form that eventually lead to AD [8].
In the past 10 years, a body of evidence has been collated suggesting that copper imbalance specifically affects a certain percentage of AD patients [9][10][11]. Copper imbalance appears to be typified by an increased level of copper in the general circulation, which can be attributed to expansion of the non-ceruloplasmin-bound (non-cp) copper fraction in serum as well as a decreased level of copper in the brain [12][13][14][15][16][17][18][19], though the proportion of labile copper (i.e., exchangeable copper relative to the copper content of the tissue) increases in the brain [20].
Though copper is highly concentrated in amyloid plaques, its concentration reduces in neurons [12][14][15][16][17][18][19][21]. A body of evidence suggests that intracellular copper deficiency in neurons could represent a possible cause of neuronal death in AD (reviewed in [22]). Beyond describing the processes of copper content dysregulation in the bloodstream (recently reviewed in [7]), it remains unclear why the concentration and distribution of copper in the brains of AD patients change, though a number of attempts have been made to interpret this complex phenomenon (reviewed in [11]). Determining how this happens may significantly contribute toward finding appropriate methods for intervening in the progression of the disease and identifying its starting point [23][24]. In this review, we compile and discuss the latest results available on one aspect of the complex puzzle of copper imbalance in AD—the brain copper deficiency.

2. Insights and Concluding Remarks                               

The grey matter and certain areas of the brain like the hippocampus that are the most damaged in AD have been reported to contain the highest levels of copper in a healthy brain [25][26]. The brains of patients with AD are copper deficient [12][14][15][16][17][18][19][27], and a dataset led to the hypothesis that this deficiency can consequently lead to channel creation in the neuron membrane, which results in apoptosis [22][27]; however, the cause of this deficiency is not yet known.

Recently, a critical, location-dependent copper dissociation constant (Kdc) was proposed as a new mechanism, featuring a shift from physiological bound metal ion pools to loose toxic pools in copper imbalance (reviewed in [11]). This hypothetical mechanism provided some clues on the key decreased copper enzymes and transporters in the AD brain that can majorly affect copper buffering and functioning in synapses during the glutamatergic transmission process. The concept proposed is applicable to Aß and APP as well as other copper proteins relevant to the AD cascade, including the prion protein and ∝-synuclein [11].

Another putative mechanism of copper deficiency in neuronal cells lies in Aß sorting and segregation within lipid rafts. Of note, Aß is produced in lipid rafts [28][29] before entering the synaptic space or being digested inside the neuron [30]. In AD, it seems that Aß production increases or its clearance decreases, and binding of copper ions to this peptide (with a high affinity for copper ions) or deposition outside the cell can lead to copper deficiency in neurons. The findings indicate that the Aß is greatly deposited in areas of the brain with the most damage. As well as this, greater deposition may cause more intense apoptosis due to greater copper deficiency.

Certain evidence suggested that microglia activation can be considered as another possible cause of copper deficiency in neurons. Copper is unevenly distributed in the brain, and some brain areas contain greater amounts of copper. One such area is the hippocampus, which is related to memory and becomes severely damaged in AD [25][31]. Neurons of this area routinely use copper to prevent excitotoxicity by NMDA receptors, and also release copper at the micromolar level after each depolarization to synapses [32][33]. Aß deposits have also been shown to activate microglia, and the activated microglia then clear amyloid from the environment [34]. Meanwhile, the activated microglia increase the expression of copper-related proteins, which consequently causes copper uptake into the microglia [35]. Also, a new study confirmed that microglia increase their intracellular copper in response to the inflammatory stimuli [36]. Therefore, it seems that if microglia are activated in the areas using copper to prevent excitotoxicity by NMDA receptors, by microglia absorbing copper from the synaptic space, copper re-uptake by neurons can be disrupted, which consequently causes a serious copper deficiency in neurons. Correspondingly, this phenomenon can cause overactivation of NMDA receptors and subsequently lead to neurodegeneration. Moreover, it was found that copper imbalance in the heart is dangerous. Loss of copper from the heart occurs in myocardial ischemia [37][38]. Recently, in an animal study, it was shown that upregulation of an intracellular copper exporter, such as copper metabolism MURR domain 1 (COMMD1), in the heart is key to exporting copper from the heart to the blood on ischemic insult [39]. Accordingly, this mechanism can also take place in the brain in AD, especially in the hippocampus. In addition, the upregulation of CTR1 in microglia can function to absorb the copper released from neurons.

NMDA receptors seem to regulate different processes in various brain regions [40][41]. Accordingly, they have different distributions in the central nervous system in terms of their type of subunit [42]. For instance, NR2A and NR2B are overexpressed in the cortex and hippocampal areas, respectively, while high NR2C expression is specific to the cerebellum area [42][43]. On the one hand, the earliest instance and highest level of damage were found to be related to the cortex and hippocampal areas, respectively, while the lowest was related to the cerebellum area [44][45]. On the other hand, the cortex and hippocampus have the highest levels of copper in the brain. Taken together, this evidence suggests that activation of microglia in the presence of copper-regulated NMDA receptors may be a significant factor in copper deficiency in neuronal cells.

In addition, the activation of microglia in areas using copper to prevent excitotoxicity by NMDA receptors can lead to copper deficiency through another mechanism. Copper reduces the phagocytic properties of microglia, which can consequently result in greater Aß deposition [46][47]. Logically, a greater increase of Aß deposition in this area would lead greater amounts of copper to be deposited out of reach of neurons. Otherwise, evidence has shown that copper intensifies Aß-mediated microglia activation, and subsequently, highly activated microglia do not play a protective role, which leads to neuronal death [48] (Figure 1). However, previous studies have shown that microglia form a barrier around small amyloid plaques, and slowing of the dystrophic neural process can be detected in areas with microglial coverage, suggesting peptide clearance by microglia protects neurons against Aß toxicity [49].

Inorganics 10 00006 g001 550

Figure 1. Postulated differences in microglia activity with either the absence or presence of a high copper concentration. When high levels of amyloid are released into the synapse, amyloid fibrils are formed and the microglia are activated, clearing the fibrils by phagocytosis (a). Releasing high levels of copper into the synapse, as copper inhibits the NMDA receptor, results in soluble A  deposits, which are then taken up by microglia via pinocytosis, causing overactivation of the microglia and inflammation (b).

In general, copper imbalance in AD, similar to the disease itself, is a complex phenomenon. In this review article, we attempted to specifically address the possible causes of copper depletion in neurons. We hypothesized that there may be two possible causes of copper depletion in neurons: first, the release of amyloid (as a copper transfer protein with a high affinity for copper) from neurons and its deposition outside neurons can trap copper outside neurons, which in turn, causes copper deficiency in neurons. Second, the uptake of copper by the activated microglia makes copper inaccessible to neurons.

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