Effect of pesticides on phosphorylation of tau protein, and its influence on Alzheimer’s disease

Table 2 Effect of organophosphates pesticides on tau protein

Type of study	Sample	Type of pesticide	Exposure data	Tau phosphory-lation	GSK-3β	PP2A	Other mechanisms	Ref.
Clinical/epidemiological studies. Cases and controls, unpaired	33 humans exposed to OPs and 33 humans without exposure	OPs	Concentration: NA. Exposure time 2 yr	Increased	NA	NA	Subjects exposed to OPs for more than 10 yr showed 97% higher serum concentration of phosphorylated tau, when compared to the control group	[53]
Experimental studies	C57BL/6 and 129/Sv mice	Paraquat	Concentration: 10 mg/kg. Exposure time for 6 wk	Increased	Increased	NA	Exposed mice showed a 67% increase in hyperphosphorylation of tau in Ser262, Ser396 and Ser404 in striata region, suggesting that paraquat may inhibit the proteosome 20S as tau overexpression occurs. Thus, it was inferred that the proteosomal activity was reduced by exposure to paraquat	[31]
Experimental studies	Wistar rats	Malathion	Concentration: 100 mg/kg. Exposure time of 14 d	Increased	Increased	Decreased	The level of hyperphosphorylated tau protein in rats with exposure was increased in Thr205 and Ser404. This result may be related to phosphatase inactivation and increased GSK-3β activity. In addition, a decrease in the expression of mRNA of PP2A was reported due to the exposure to malathion	[33]
Experimental studies	MAP-rich tubulin from Sus Scrofa from porcine brain	Chlorpyrifo- oxon, paraoxon and diazoxon	Concentration: 100 μM. Exposure time of 48 h	Increased	NA	NA	Cross-link was formed between MAP-tubulin (alpha), at residues Lys163, Lys336 and Asp98 of MAP with residues Glu158 and Lys115 of tubulin beta. Lys336 and 163 cross-links covalently joined with tau protein, forming Lys-adduct, which resulted in unstable microtubules	[36]
Experimental studies	FVB and C57BL/6 mice	DFP	Concentration: 5 mg/kg. Exposure time of 15 d	Increased	NA	NA	Exposure increased Cdk5 activity by converting p35 to p25. Exposure to DFP increased 15.5 ± 2 times the phosphorylation of Cdk5 in Thr205 and therefore of tau protein, thereby inducing neurological effects in the striatum and hippocampus	[37]
Experimental studies	Wistar rats	Chlorpyrifos- oxon	Range of concentration: 1 to 100 nM. Chronic exposure	Not modified	NA	NA	No significant changes in tau protein levels from chlorpyrifos exposure	[49]
Experimental studies	Transgenic AD model rats	Chlorpyrifos	Concentration: 3 and 10 mg/kg. Exposure time of 21 d	Not modified	NA	NA	No changes in hyperphosphorylation of rat tau protein with exposure to control rats	[50]
Experimental studies	Wistar rats	Paraquat	Concentration: 0.1 mg/kg. Exposure time of 4 mo	Increased	NA	NA	In exposed rats, neurofibrillary tangle was formed in the compact pars of the substantia nigra region and in extracellular neuritic plaques as a result of a neuroinflammatory cascade by the activation of microglia and astrocytes, which increased tau phosphorylation	[51]
Experimental studies	NMRI mouse	Chlorpyrifos	Concentration: 0.1, 1.0, 5.0 mg/kg. Single dose	Not modified	NA	NA	No significant differences were observed in tau levels due to exposure to this pesticide	[54]
Experimental studies	Cell culture in septal SN56 basal forebrain cholinergic neurons	Chlorpyrifos	Concentration: 30 μM. 24 h and 14 d exposure time	Increased	Increased	NA	Exposure to OPs upregulated the expression of GSK-3β and its activity, thereby increasing the phosphorylation of tau	[55]
Experimental studies	Cell culture hiPSC and Wistar rats	DFP	Cell culture concentration: 200 nM. Exposure time for 2 d. Murine concentration: 1.5 mg/kg. Exposure time for 7 d	Increased	NA	NA	Exposure was associated with increased tau phosphorylation and decreased microtubule acetylation which decreased its stability. In the CA3 region of the hippocampus, an increase in tau phosphorylation was observed, indicating that it is a vulnerable site for the action of OPs	[56]
Experimental studies	Wistar rats	Dichlorvos	Concentration: 200 mg/kg. Single dose	Increased	NA	NA	Increased phosphorylation of MAP-2 and tubulin. Exposure increased phosphorylation and stimulated increased activity of calcium-dependent kinases/calmodulin and cAMP. Microtubules were destabilized, resulting in changes in morphology and increased neurotoxicity in exposed rats	[57]
Review studies	Multiple studies	Malathion	Range of concentration: 97 to 775 μM in model MCF-7. Concentration: 100 mg/kg in Wistar rats. Single dose	Increased	Increased	Decreased	MAP-2 hyperphosphorylation was observed, especially of KGS amino acids. This may be related to ubiquitination and protein degradation with these amino acids. Tau hyperphosphorylation is associated with GSK-3β kinase activation and phosphatase inhibition	[39]
Review studies	Multiple studies	Paraquat	NA	Increased	NA	NA	Paraquat raised levels of oxidative stress, thereby inducing phosphorylation of tau, based on several studies conducted in cell cultures	[41]
Review studies	Multiple studies	OPs	NA	Increased	NA	NA	Exposure to OPs increased Cdk5 hyperactivity and tau hyperphosphorylation. This disrupted the structure and function of microtubules in patients with AD, thereby affecting axonal transport. Even low levels of exposure caused changes in microtubules	[58]
Review studies	Multiple studies	OPs	NA	Increased	Increased	NA	Increased the level of reactivity autoantibodies against microtubule-associated proteins and tau-regulatory proteins (MAPT and MAP-2)	[59]
Review studies	Multiple studies	OPs ester	Different conditions	Increased	NA	NA	The activities of kinase enzymes were altered phosphorylation of Ser or Thr. This enhanced the aggregation of proteins and the formation of neurofibrils, thereby inducing neurodegeneration. The target enzymes are calcium/calmodulin dependent kinases that increase phosphorylation of MAP-2 and tau protein	[60]
Review studies	Multiple studies	Methamido-phos, trichlorfon, dichlorvos, chlorpyrifos	Different conditions	Increased	NA	NA	Increased activity of calcium-dependent kinases/calmodulin, forming aberrations in the phosphorylation of cytoskeleton proteins, a common feature in neurodegenerative diseases	[61]

OPs: Organophosphates; NA: Not available; DFP: Diisopropyl fluorophosphate; Thr: Threonine; K: Lysine; G: Glycine; S: Serine; Ser: Serine; mRNA: Messenger ribonucleic acid; hiPSC: Human-induced pluripotent stem cells; Lys: Lysine; Asp: Aspartate; Glu: Glutamate; MAPT: Microtubule associated protein tau; AD: Alzheimer’s disease; TCDD: 2,3,7,8 tetrachlorodibenzo-p-dioxin; GSK-3β: Glycogen synthase kinase 3 beta; MAP-2: Microtubules-2; Cdk5: Cyclin-dependent kinase 5; cAMP: Cyclic adenosine monophosphate; PP2A: Protein phosphatase-2A.