Oxidative Medicine and Cellular Longevity

Review Article

Metals and Neuronal Metal Binding Proteins Implicated in Alzheimer’s Disease

Table 1

Effect of metal ions on selected metal-binding proteins implicated in AD.


Protein	Metal	Effect	Model	Reference

Aβ	Cu²⁺	Modulates aggregation. Presence of Cu²⁺ in Aβ aggregates decreases toxicity; however, presence of Cu²⁺ in soluble Aβ accelerates cell death. Substoichiometric levels of Cu²⁺ render Aβ aggregates more toxic.	Synthetic Aβ, HEK cells, primary hippocampal cells, and PC12 cells	[49, 52–55, 57–59]
	Cu²⁺	Increases oxidative stress and neurotoxicity.	Synthetic Aβ, primary neuronal cells	[60, 63, 126, 127]
	Zn²⁺	Modulates aggregation. Zn²⁺ leads to less toxic Aβ aggregates.	Synthetic Aβ, HEK cells, and primary cortical cells	[49, 53, 54, 57]
	Fe²⁺	Modulates aggregation promoting the formation of annular protofibrils.	Synthetic Aβ	[49, 68, 69]
		Increases protein levels by disruption of APP processing.	Primary cortical neurons, APP/PS1 mice model, and HEK cells	[67]
		Increases oxidative stress.	M17 neuroblastoma cells, Drosophila model	[61, 62]

Tau	Cu²⁺	Modulates phosphorylation.	Tg-AD mice model, SH-SY5Y cells, and AD mice model	[81, 82]
	Cu²⁺	Modulates aggregation.	Peptide from tau first microtubule-binding repeat	[80]
	Zn²⁺	Induces phosphorylation through Zn²⁺ PP2A inhibition.	Rat brain slice cultures, primary neuronal cells	[72]
	Zn²⁺	Induces fibril formation via disulfide cross-linking.	Recombinant tau protein	[73]
	Fe²⁺	Modulates aggregation.	Recombinant tau protein, isolated hyperphosphorylated tau from human AD brain tissue	[74, 75]
	Fe²⁺	Induces imbalance in Cdk5/p25 function that causes a decrease in tau phosphorylation and an increase in oxidative stress.	Primary hippocampal cells	[78, 128]

APP	Cu²⁺	Increases APP expression levels and Aβ secretion. Promotes APP trafficking and its redistribution.	SH-SY5Y cells, polarized epithelial cells, MDCK-APP-cherry cells, primary cortical neurons, N2a cells, and APP/PS1 mouse model	[81, 83, 85, 86]
	Cu²⁺	Increases oxidative stress. Cu²⁺-metalated APP ectodomain promotes neuronal cell death.	Recombinant APP protein and mutants, primary neuronal cells	[90, 91]
	Zn²⁺	Inhibits ferroxidase activity.	Human brain tissue	[92]
	Zn²⁺	Increases APP expression levels and amyloidogenic cleavage that leads to accumulation of Aβ.	SH-SY5Y cells, APP/PS1 mice model	[84]
	Fe²⁺	APP interacts with ferroportin and promotes iron export.	Human brain tissue, HEK293 cells	[92, 93]

Presenilin	Ca²⁺	Overexpression of PS1 decreases Ca²⁺ release from ER and downregulates Ca²⁺-dependent mitochondrial transport proteins. Expression of PPS1 M146V causes inhibition of Ca²⁺ channels.	HEK293 cells, human brain tissue, SH-SY5Y cells, SK-N-SH cells, and APPswe/PS1dE9 mice model	[95–97]

MT3	Cu²⁺ Zn²⁺	Decreases protein levels.	Human brain tissue, Tg2576 mouse model	[100, 101]
		MT3 interacts with Aβ inhibiting/modulating Aβ aggregation and cytotoxicity.	Recombinant MT3 protein and synthetic Aβ, SH-SY5Y cells, primary cortical cells, and Tg2576 mouse model	[104–107]
		Metal swapping between MT3 and Aβ lowers ROS production and decreases neurotoxicity.	Recombinant MT3 protein and synthetic Aβ, SH-SY5Y cells	[109]
		MT3 increases sAPPα levels and reduces Aβ production.	N2a Swedish APP cells	[102]

ZnTs	Zn²⁺	Increases expression levels and colocalization with amyloid plaques.	APP/PS1 mouse model, human brain tissue	[110–112, 129]

ProSAP/Shank scaffold proteins	Zn²⁺	Zn²⁺ sequestering by Aβ decreases Shank1 and ProSAP27Shank3 protein levels and promotes synapse loss by disruption of Homer1b and Shank1 scaffold.	Primary hippocampal cells, human brain tissue, and Cos7 cells	[115–117]
ProSAP/Shank scaffold proteins	Ca²⁺	Homers 2 and 3 interact with APP inhibiting APP processing and consequently reducing Aβ secretion.	HEK293 cells, C57/Black6 mouse model	[130, 131]

Ferritin	Fe²⁺	Increases protein levels. Present within and around amyloid plaques and neurofibrillary tangles.	Human brain tissue	[119–121]

S100B	Ca²⁺	Increased expression of S100B contributes to overexpressing βAPP in diffuse amyloid deposits.	Primary neuron cells	[132]
S100B	Zn²⁺ Ca²⁺	S100B interacts with tau resulting in the inhibition of tau phosphorylation via Ca²⁺/calmodulin-dependent kinase II.	Bovine S100B, SH-SY5Y cells	[133, 134]

S100A9	Ca²⁺	Increases protein levels. Present near amyloid plaques. Interacts with Aβ In vitro and forms linear and annular aggregates. Knockout of the S100A9 gene reduces neuropathology due to reduced Aβ and APP C-terminal levels.	Human brain tissues, Tg2576 mice model, SH-SY5Y cells, and S100A9 recombinant protein	[135–139]

S100A7	Ca²⁺	Expression of exogenous S100A7 inhibits Aβ production and promotes α-secretase activity.	Primary corticohippocampal cells	[140]