Role of neurotoxicants in the pathogenesis of Alzheimer’s disease: a mechanistic insight

Figures & data

Figure 1. Aβ-mediated neurotoxicity in Alzheimer’s disease. The major neurotoxic effects of Aβ_1-42 peptides in the pathological development of AD are illustrated in this diagram. That includes the formation of soluble Aβ oligomers, amyloid plaques and neurofibrillary tangles, generation of reactive oxygen species, the imbalanced concentration of metal ions, and functional impairment of mitochondria, brain immune cells, and neurotransmission. Through these mechanisms, toxic Aβ induces oxidative stress, death of neurons, synaptic malfunction, neuroinflammation, and exacerbates the abnormal protein aggregation in critical brain regions.

Figure 2. Major neurotoxicants at the onset and progression of Alzheimer’s disease. The abnormal build-up of amyloid-beta protein that generates amyloid plaques and hyperphosphorylated tau protein that forms neurofibrillary tangles in and around neurons are apparent at the onset of Alzheimer’s disease. Multiple neurotoxicants such as metals, pesticides, and nanoparticles have been found to augment the formation of Aβ aggregates and NFTs through different mechanisms. These neurotoxicants produce oxidative stress in neurons that trigger Aβ peptide formation and hyperphosphorylate tau protein. Neurotoxicants stabilise APP expression and β- secretase enzyme activities; on the other hand, they disrupt the functions of antioxidant enzymes, Aβ degrading proteins, and receptors that result in amyloid plaque formation. Neurotoxicants bind with tau, dissociate them from microtubules and increase their hyperphosphorylation. Enzymes that dephosphorylate tau protein are also inhibited by neurotoxicants that ultimately leads to the formation of neurofibrillary tangles.

Table 1. Signalling pathways modulated by neurotoxicants in the pathogenesis of Alzheimer’s disease.

Sl	Neurotoxic agents	Study type	Molecular targets	Mechanism of action	References
Wnt signalling pathway
1	Antimony (Sb)	In vitro	β-catenin and GSK-3β	Activation of GSK-3β and suppression of β-catenin; reduction of Wnt/β-catenin activities	[53]
2	Arsenic (As)	In vitro	GSK-3β	Increased activity of GSK-3β kinase	[54]
3	Bisphenol-A	In vitro In vivo	Dkk1, GSK-3β, Wnt-1, Wnt-3, LRP-5/6, Dvl, LEF-1, TCF, β-catenin and cyclin D-1	Upregulation of Wnt signalling antagonists Dkk1 and GSK-3β;decreased level of Wnt-1, Wnt-3, LRP-5/6, Dvl, β-catenin, Wnt target gene cyclin D-1, and nuclear transcription factor LEF-1, TCF; inhibition of the Wnt/β-catenin pathway	[55]
4	Copper (Cu)	In vitro	GSK-3β	Increased activity of GSK-3β; phosphorylation of APP and tau	[56,57]
5	Iron (Fe)	In vitro	GSK-3β	Induction of oxidative stress; activation of GSK-3β kinase; hyperphosphorylation of tau	[57]
6	Methyl mercury (MeHg)	In vitro	GSK-3β	Higher expression of GSK-3β; suppression of neuronal proliferation and development	[58]
7	MPP+	In vitro	Dkk1	Induction of Dkk1; inhibition of the canonical Wnt pathway	[59]
8	Paraquat (PQ)	In vivo	GSK-3β	Enhanced expression and activity of GSK-3β; formation of neurofibrillary tangles (NFT); disruption in neuronal function	[60]
9	Pesticides – Deltamethrin & Carbofuran	In vivo In vitro	GSK-3β	Increased activation of GSK-3β; Tau pathology; cognitive injury	[61]
10	Silica nanoparticles (SiNPs)	In vitro	GSK-3β	Stimulation of GSK-3β activities; pathological deposition of Aβ; increased in tau phosphorylation	[62]
Autophagy and mTOR signalling
1	Arsenic (As)	In vivo	mTOR, Beclin1, LC3, Atg, p62	Increased Beclin1, LC3, and Atg12 and decreased mTOR proteins activated autophagy; increased p62 led to autophagy dysfunction	[63]
2	Cadmium (Cd)	In vitro	Ca^2+ ion and mTOR	Increased level of intracellular Ca^2+; activation of mTOR; induction of apoptotic cell death	[64]
3	Copper (Cu)	In vitro	Autophagic pathway	Enhanced autophagic influx; defect in autophagic activities; neuronal cell death	[65]
4	Iron (Fe)	In vitro	Autophagic pathway	Increased oxidative stress concomitant with increased autophagy activation	[66]
5	Methyl mercury (MeHg)	In vitro	LC3II, P62 and lysosomes	Accumulation of autophagosomes; defected autophagy as well as impaired lysosomal activity; neuronal cell death	[67]
6	Manganese (Mn)	In vivo	Beclin1, LC3II, mTOR, and lysosome	Activation of mTOR; dysregulation in autophagy; decreased expression of beclin1 and LC3II; defected lysosome structure	[68]
		In vitro	Lysosome	Enhanced lysosomal permeabilization; cell death	[69]
7	Lead (Pb)	In vivo	Autophagic pathway	Upregulation of autophagosome formation and autophagic activity; excessive autophagy leading to cellular death	[70]
PKC signalling
1	Aluminium (Al)	In vitro In vivo	PKC	Remarkable decrease in PKC concentration	[71]
2	Lead (Pb)	Literature review	Ca^2+ and PKC	Interaction with PKC through Ca^2+ substitution; activation of PKC at lower concentration	[72]
		In vitro	PKC	Inhibition of PKC at higher concentration	[73]
		In vitro	PKC	Interference with the catalytic domain of PKC that limits their function	[74]
3	Mercury (Hg)	In vitro	PKC	Inhibition of PKC activity	[75]
4	Methyl mercury (MeHg)	In vitro	PKC	Inhibition of PKC function	[76]
5	Nickel (Ni)	In vitro	Genes of PKCγ, PKCζ, RACK-1, and PKCδ binding protein	Reduced transcription the genes encoding PKCγ, PKCζ, RACK-1, and PKCδ binding protein	[75]

Figure 3. Inhibition of the Wnt/β-catenin signalling by neurotoxicants. In normal brain, when Wnt signalling is switched on, GSK-3β is found to be inactive, and tau protein remains dephosphorylated. β-catenin translocation in the nucleus activates Wnt target genes that inhibit the development of Aβ_1–42. In the presence of various neurotoxicants (Fe, Cu, As, Pb, MeHg, BPA, pesticides, and NPs), Dkk1 and GSK-3β, the inhibitors of Wnt signalling cascade become activated. Activation of Wnt proteins, LRP 5/6, and β-catenin are also inhibited by some neurotoxicants (BPA, Sb). β-catenin is phosphorylated by GSK-3β and undergoes proteasomal degradation. As a result, Wnt signalling is shut off, leading to tau hyperphosphorylation and Aβ_1–42 production and aggregation that aids AD pathology.

Figure 4. Dysregulation of autophagy and mTOR signalling by neurotoxicants. Although autophagy and mTOR signalling are vital for the healthy and normal functioning of neurons, some neurotoxicants interrupt their regulation. Excessive activation of mTOR signalling through neurotoxicants (Mn, Cd) results in mitophagy and neuronal apoptosis that inhibits normal autophagic function. However, autophagy-related proteins, including ATG, Beclin, LC3II, etc. and different autophagic steps are negatively influenced by neurotoxicants (Fe, Cu, Mn, As, Pb, MeHg), leading to the uncontrolled autophagic influx. Some neurotoxicants (As, MeHg, Mn) damage lysosomal structure, which after fusion with autophagosome, produces immature autophagolysosome vacuoles (AVs) and halt the degradation of autophagolysosomes. Finally, increased accumulation of AVs in neurons triggers neuronal death.

Figure 5. Alterations in PKC signalling by neurotoxicants. PKC signalling is associated with multiple functions, including the formation of sAPPα and inhibition of GSK-3β that decreases Aβ production and tau hyperphosphorylation. At the same time, some neurotoxic agents (Al, Pb, Ni, Hg, MeHg) interfere with PKC enzyme expressions and activities that alter normal PKC signalling. This, in turn, enhances Aβ_1–42 production and directly affects PKC signalling.

Table 2. Role of neurotoxin-induced cellular stresses in the progression of Alzheimer’s disease.

Sl	Neurotoxic agent	Study type	Molecular targets	Key modulating effects	References
Toxic heavy metals
1	Aluminium (Al)	In vitro In vivo	Hippocampal and frontal brain	Interruption in biometal homeostasis in neuron cells that produce oxidative damage; alteration in signalling pathways that promote neuropathology	[107]
		In vitro In vivo	Neurons	Induction of oxidative stress that stimulates Aβ and NFT accumulation	[108,109]
		In vitro In vivo	Aβ catalysing enzyme and antioxidant PP2A enzyme	Inhibition of Aβ catabolizing enzyme and PP2A enzyme activities; reduction of Aβ degradation; stimulation of NFT formation	[110,111,112]
2	Arsenic (As)	Literature review	Glutathione (GSH)	Binding with –SH groups of glutathione; production of excessive H2O2	[107]
4	Cadmium (Cd)	In vitro	Ca^2+	Disruption of cytoplasmic and nuclear Ca^2+ homeostasis; modulation of cellular processes	[113]
		In vitro	Antioxidant enzymes: GSH, catalase, and SOD	Inhibition of GSH, catalase, and SOD activities; induction of cellular oxidative stress and lipid peroxidation	[114]
4	Calcium (Ca)	Literature review	Enzymatic process	Lipid peroxidation, protein destruction and neuronal death promoted by excessive intracellular Ca influx	[115]
5	Copper (Cu)	In vitro	Aβ	Formation of Cu-Aβ conjugate; production of H2O2	[107]
		In vivo	τ-protein	Induction of H2O2; formation of Aβ and hyperphosphorylated τ	[116]
6	Iron (Fe)	Literature review	CNS	Overproduction of ROS due to high Fe concentration;	[107]
		Literature review	Mitochondria	Induction of oxidative stress; disruption of mitochondrial function; initiation of cytotoxic reactions.	[117]
7	Lead (Pb)	In vitro	DNA methylating enzymes	Decreased expression of DNA methylating enzymes that enhance APP expression and attenuates Aβ elimination	[107]
		Literature review	Antioxidant enzymes and metal cofactors	Binding to metal cofactors and –SH groups of antioxidant enzymes; disruption of various processes which elevate oxidative stress and mitochondria dysfunction	[105]
11	Manganese (Mn)	In vitro In vivo	Ca^2+ and mitochondria	Obstruction of Ca^2+ efflux in mitochondria; impediment in mitochondrial Ca^2+ homeostasis	[117]
		Literature review	CNS	Increased ROS production; impaired mitochondrial function; reduction in cellular antioxidant mechanism	[107]
		In vitro	Mitochondria	Inhibition of ETC; reduction in oxidative phosphorylation and ATP formation; disruption in mitochondrial membrane permeability	[117]
8	Mercury (Hg)	In vitro	Neuron cells	Induction of oxidative stress via ROS production; increased Aβ and τ pathology	[118]
10	Methylmercury (MeHg)	In vitro & Literature review	–SH group containing proteins and antioxidative enzymes	Alteration in the oxidative state of –SH containing proteins and antioxidant enzymes; modulation of their function	[117]
11	Zinc (Zn)	Literature review	ETC	Intervention in ETC complex-III; stimulation of ROS production; induction of mitochondrial dysfunction and neuronal death	[119]
Pesticides and herbicides
1	Organochlorines, organophosphates and bipyridal herbicides	In vivo & literature study	CNS	Generation of free radicals that increases cellular oxidative stress	[120,121]
Industrial chemical
1	Bisphenol-A (BPA)	In vitro	Neurons	Disruption in intracellular Ca^2+ homeostasis, endoplasmic reticulum and mitochondrial dysfunction; decreased level of antioxidant enzymes, e.g. GSS and CAT	[122]
		In vivo	CNS	Damaged neurons and organelles	[123]
			Functional proteins	Lipid peroxidation and alteration in proteins expression level	[124]
Nanoparticles
1	Copper nanoparticles (nano-CuO)	In vitro In vivo	Antioxidant enzymes – SOD and GSH-Px	Production of ROS and MDA; inhibit SOD and GSH-Px activity	[125]
2	Silica nanoparticles (SiNPs)	In vitro	Neuronal cell	Production of intracellular ROS; induction of apoptosis	[62]
3	Titanium dioxide nanoparticles (TiO2 NPs)	In vitro In vivo	Hippocampal cell	Induction of cellular oxidative stress, glial reactivity and apoptosis	[126]

Table 3. Effects of neurotoxic agents on iGluRs and mGluRs in the onset and progression of Alzheimer’s disease.

SL	Neurotoxic agents	Study type	Molecular targets	Key modulating effects	References
Excitatory amino acids
1	BMAA	In vitro In vivo	AMPAR/KAR, NMDAR, mGluR5	Neuroinflammation, oxidative stress, apoptosis, cognitive impairment	[129]
2	Glutamate	In vitro In vivo	iGluR and mGluR	Induction of apoptosis, autophagy mitochondrial dysfunction, oxidative damage and neuroinflammation.	[130,131,132,25]
3	Homocysteine	In vivo	NMDAR, mGluR1	Synaptic dysfunction, oxidative stress, neurochemical imbalance, apoptosis/necrosis, neuronal cell death	[133,134]
Excitatory amino acid agonist
1	Domoic acid (DomA)	In vivo	iGLuR	Neuroinflammation, mitochondrial dysfunction, production of ROS	[135]
2	Kainic acid	In vitro In vivo	iGluR	Production of ROS, mitochondrial dysfunction, neuroinflammation and neuronal autophagy	[136]
CNS stimulant
1	Harmaline	In-vivo	NMDARs, AMPARs and mGluR1	Disturbance in motor function, production of tremors	[137]
Industrial organic compound
1	Bisphenol-A	In vitro	NMDAR, AMPAR	Production of neurotoxicity	[138,139,139]
Inorganic compound
1	Ammonia	In vivo	NMDAR	Reduction of glutamine synthetase activity, decreased elimination of ammonia from the brain	[140]
2	Hydrogen peroxide	In vitro	NMDAR	Alteration in synaptic transmission, oxidative stress, mitochondrial dysfunction, cytotoxicity, apoptosis, neuronal cell death	[141]
3	Mercury	In vitro	NMDAR	Mitochondrial dysfunction, oxidative stress, neuroinflammation, apoptosis, neuronal cell death	[28,142,143]
4	Sodium azide	In vitro	NMDAR	Mitochondrial dysfunction, oxidative stress, neuroinflammation, neuronal cell death	[144]

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Data availability statement

Data available on request from the authors.