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

Table 1 Effect of organochlorine 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. Cohort	13 postmortem brains of humans without exposure, and 4 postmortem brains of humans with exposure	OCs	Concentration: NA. Exposure time: From 0 to 10 yr	Increased	NA	NA	Exposure altered mitochondrial genes encoding MAPT and MAP1B. These are associated with MAPT phosphorylation and neurite formation that contributed to the development of tauopathies	[44]
Clinical/epidemiological studies. Cross-sectional	90 subjects with PD, and 90 healthy subjects	δ-HCH	Concentration: NA. Exposure time: NA	NA	NA	NA	Exposure was associated with MAPT rs16940758 polymorphism which was related to tau aggregation	[45]
Experimental studies	Strains of Caenorhabditis elegans (N2 BR5270)	DDT	Concentration: 3 μM. Exposure time of 2 h	Increased	NA	NA	DDT exacerbated tau protein toxicity, reduced mitochondrial respiration, and induced apoptosis	[42]
Experimental studies	Strains of Caenorhabditis elegans (N2 BR5271)	DDT	Concentration: 3 μM. Exposure time of 2 h	Increased	NA	NA	Exposure to DDT increased tau protein aggregation and modified mitochondrial respiration	[46]
Experimental studies	Female largemouth bass	Dieldrin	Concentration: 3.0 mg/kg. Exposure time of 57 d	NA	NA	Decreased	Increased expression of proteins in hypothalamus such as Snap25, Cytc, Eno1, Hba1, and H2bb. These proteins were elevated in the pathophysiology of mice with AD and were associated with tau protein. Additionally, downregulation of MAPT was observed, which affected phosphatase activity	[47]
Experimental studies	Wistar rats	Chlordane	Range of concentration: 1 to 100 nM. Chronic exposure	Not modified	NA	NA	No significant changes in tau protein levels from exposure to chlordane	[49]
Review studies	Multiple studies	TCDD	Range of concentration: 5-23 ppt. Single dose	Increased	Increased	NA	Increased intracellular calcium levels and tau phosphorylation in neurons through overexpression of GSK-3β and hence its enzymatic activity	[48]

OCs: Organochlorine; NA: Not available; MAPT: Microtubule associated protein tau; δ-HCH: δ-hexachlorocyclohexane; DDT: Dichlorodiphenyltrichloroethan; AD: Alzheimer’s disease; TCDD: 2,3,7,8 tetrachlorodibenzo-p-dioxin; GSK-3β: Glycogen synthase kinase 3 beta; PD: Parkinson disease; ppt: Parts per thousand; PP2A: Protein phosphatase-2A.

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.

Table 3 Effects of carbamate pesticides on tau protein

Type of study	Sample	Type of pesticide	Exposure data	Tau phosphorylation	GSK-3β	PP2A	Other mechanisms	Ref.
Experimental studies	C57BL/6 and 129/Sv mice	Maneb	Concentration: 30 mg/kg. Exposure time for 6 wk	Decreased	Decreased	NA	No changes in tau phosphorylation. However, if combined with paraquat, tau phosphorylation was enhanced in Ser202 (38% more), Ser262 (28% more) and Ser396/404 (141% more)	[31]
Experimental studies	Sprague-Dawly rats	Carbofuran	Concentration: 1 mg/kg. Exposure time of 28 d	Increased	Increased	Decreased	Increased phosphorylation of tau was observed in Ser198/199/202, Thr205 and Ser404. In addition, there was an increase in GSK-3β and a decrease in PP2A	[32]
Experimental studies	NMRI mouse	Carbaryl	Concentrations: 0.5, 5.0, 20.0 mg/kg. Single dose	Increased	NA	NA	In the hippocampus, levels of phosphorylated tau increased by 135% in rats exposed to low, medium and high doses. In cerebral cortex, there was oscillating increase of 155% to 210% in tau phosphorylation	[54]
Experimental studies	Sprague-Dawly rats	Deltametrin (P)/carbofuran (Cs)	Concentration: NA. Exposure time for 28 d	Increased	Increased	Decreased	Exposure induced tau hyperphosphorylation and GSK-3β activation, as well as PP2A phosphatase inhibition	[63]
Review studies	Multiple studies	Cs	NA	Increased	Increased	NA	Exposure induced increased activity of kinase, thereby increasing phosphorylation of tau protein	[62]
Review studies	Multiple studies	Pyridine carbamate	Concentrations: 15.7 μM. Single dose	Decreased	NA	NA	An inhibitory effect on phosphorylation was observed. This prevented the aggregation of tau protein	[64]

Ser: Serine; Thr: Treonine; GSK-3β: Glycogen synthase kinase 3 beta; PP2A: Protein phosphatase-2A; NA: Not available; Cs: Carbamate; Ps: Pyrethroids.

Table 4 Effects of pyrethroid pesticides on tau protein

Type of study	Sample	Type of pesticide	Exposure data	Tau phosphorylation	GSK-3β	PP2A	Other mechanisms	Ref.
Experimental studies	Sprague-Dawly rats	Deltamethrin	Concentration: 12.5 mg/kg. Exposure time for 28 d	Increased	Increased	Decreased	Increased phosphorylation of tau was observed in Ser198/199/202, Thr205 and Ser404	[32]
Experimental studies	Wistar rats	Cyfluthrin, imiprothrin, prallethrin	Concentrations:25%, 50% and 75%. Exposure time of 45 d	Increased	Increased	Decreased	Higher immunoreactivity of tau occurred in the hippocampus with high exposures to Ps. For medium and low doses, low immunoreactivity occurred. On the other hand, the activity of GSK- 3β was increased, while that of PP2A 2 was decreased	[34]
Experimental studies	Wistar rats	Cypermethrin	Concentration: 10 mg/kg and 25 mg/kg. Exposure time for 2, 3 and 6 wk	Increased	Increased	NA	In weaned exposed rats, tau phosphorylation increased in frontal cortex and hippocampus. This was induced by an increase in GSK-3β activity. Furthermore, increased neuroinflammation was observed with increased production of IL-1β	[69]
Review studies	Multiple studies	Ps	NA	Increased	Increased	NA	Exposure to Ps induced increased kinase activity, thereby increasing the phosphorylation of tau protein	[62]

Ps: Pyrethroid; IL: Interleukin; GSK-3β: Glycogen synthase kinase 3 beta; PP2A: Protein phosphatase-2A; NA: Not available.

Table 5 Effects of neonicotinoid pesticides on tau protein

Type of study	Sample	Type of pesticide	Exposure data	Tau phosphorylation	GSK-3β	PP2A	Other mechanisms	Ref.
Clinical/epidemiological studies. Clinical case	Accidental intake with Ns	Imidacloprid and thiamethoxam	Concentration: NA. Single dose	NA	NA	NA	The metabolite desnitro-imidacloprid activated the flow of intracellular calcium, thereby altering the response of kinase enzymes, and causing an excitatory neurological phase	[22]
Experimental studies	Primary cultures of cerebellar neurons from neonatal Sprague-Dawly rats	Acetamiprid imidacloprid	Concentrations: 1-100 μM. Exposure time of 600 s	NA	NA	NA	Exposure to Ns increased the influx of Ca2+ in cerebellar neurons. These pesticides excited cerebellar neurons to a degree similar to that from nicotine exposure. The influx of calcium ions activated the VDCC	[70]
Experimental studies	Human neural cells	Desnitro-imidacloprid	Concentration: 50 μM. Exposure time of 48 h	Increased	Increased	Decreased	Activation of Wnt signal pathway. Exposure induced tau hyperphosphorylation by a GSK-3β response, this enzyme is associated with Beta catenin activity. Exposure to this Ns induced watered-down expression that regulated tau hyperphosphorylation and apoptotic responses that impacted synaptotoxicity	[71]

Ns: Neonicotinoid; GSK-3β: Glycogen synthase kinase 3 beta; PP2A: Protein phosphatase-2A; NA: Not available; VDCC: Voltage-dependent calcium channels.

Table 6 Effect of pesticides on cognitive processes

Type of study	Sample	Type of pesticide	Exposure data	Cognitive implications	Ref.
Clinical/epidemiological studies. Cross-sectional	90 subjects with PD and 90 healthy subjects	OCs: δ-HCH	Concentration: NA. Exposure time NA	MMSE1 values in subjects with PD and without exposure to OCs: 27.66 ± 4.63. MMSE1 values in healthy subjects with exposure to OCs: 24.33 ± 4.31	[45]
Clinical/epidemiological studies. Cohort	13 postmortem brains of subjects without exposure and 4 postmortem brains of subjects with exposure	OCs	Concentration: NA. Exposure time: from 0 to 10 yr	Last CASI1 score of subjects without exposure: 67.9 ± 24.4. Last CASI1 score of subjects with exposure: 41.6 ± 22.8	[44]
Experimental studies	Strains of Caenorhabditis elegans (N2 BR5271)	OCs: DDT	Concentration: 3 μM. Exposure time of 2 h	No significant differences reported in Associative Learning Paradigm tests	[46]
Experimental studies	Wistar rats	OCs: Chlordane	Range of concentration: 1 to 100 nM. Chronic exposure	Exposure did not affect results of tests that measured spatial memory	[49]
Review studies	Multiple studies	OCs: TCDD	Range of concentration: 5 to 23 ppt. Single dose	Decreased performance in verbal and nonverbal memory tests	[48]
Clinical/epidemiological studies. Cases and controls, unpaired	33 subjects exposed to OPs and 33 subjects without exposure	OPs	Concentration: NA. Exposure time 2 yr	87% of exposed subjects had cognitive impairment. Exposure to OPs for 10 yr increased the risk of cognitive decline 17 times	[53]
Experimental studies	Wistar rats	OPs: Chlorpyrifos- oxon	Range of concentration: 1 to 100 nM. Chronic exposure	Rats exposed to OPs showed deterioration of spatial memory	[49]
Experimental studies	NMRI mouse	OPs: Chlorpyrifos	Concentration: 0.1, 1.0, 5.0 mg/kg. Single dose	Decreased locomotion response and novelty were observed in rats exposed to this OPs	[54]
Experimental studies	Transgenic AD model rats	OPs: Chlorpyrifos	Concentrations: 3 and 10 mg/kg. Exposure time of 21 d	Exposure was associated with accelerated cognitive impairment in male rats, as indicated in memory and recognition tests	[50]
Experimental studies	Wistar rats	OPs: Malathion	Concentration: 100 mg/kg. Exposure time of 14 d	Decrease in spatial memory (evaluated using Morris water maze). This decrease was related to tau hyperphosphorylation	[33]
Experimental studies	Cell culture hiPSC and Wistar rats	OPs: DFP	Cell culture concentration: 200 nM. Exposure time for 2 d. Murine concentration: 1.5 mg/kg. Exposure time for 7 d	Slight decreases in learning and memory tests in the Morris water maze tests, and in 0 new object recognition	[56]
Review studies	Multiple studies	OPs	Different conditions	Lower perfomance in MMSE was associated with the exposure, with a modestly increased risk of MCD	[58]
Review studies	Multiple studies	OPs	NA	Exposure produced psychotic episodes, and alterations in attention, memory, problem solving, abstraction and cognitive flexibility	[59]
Review studies	Multiple studies	OPs ester	Different conditions	Decreased attention, visual memory, persistent and longer cognitive dysfunction and short-term memory	[60]
Experimental studies	Sprague-Dawly rats	Cs: Carbofuran	Concentration: 1 mg/kg. Exposure time of 28 d	Rats exposed to this pesticide took longer time to solve the Morris water maze, relative to the control group	[32]
Experimental studies	NMRI mouse	Cs: Carbaryl	Concentrations: 0.5, 5.0, 20.0 mg/kg. Single dose	Decreased locomotion response and response to novelty test in rats exposed to this pesticide	[54]
Experimental studies	Sprague-Dawly rats	Cs: Carbofuran	Concentration: NA. Exposure time for 28 d	Exposed rats had longer escape latency time in the Morris water maze test. Exposure was related to spatial memory deficit	[63]
Experimental studies	Sprague-Dawly rats	Ps: Deltamethrin	Concentration: 12.5 mg/kg. Exposure time for 28 d	Rats exposed to this pesticide took longer time to solve the Morris water maze, relative to the control group	[32]
Experimental studies	Wistar rats	Ps: Cypermethrin	Concentration: 10 mg/kg and 25 mg/kg. Exposure time for 2, 3 and 6 wk	Cognitive impairment was induced; deficiencies in learning and memory of exposed rats occurred. These changes may be related to changes in calcium-dependent kinases and calmodulin	[69]
Experimental studies	Wistar rats	Ps: Cyfluthrin. Imiprothrin and Prallethrin	Concentrations: 25%, 50% and 75%. Exposure time of 45 d	Rats with the highest P exposure had higher cognitive impairment, when compared to control rats and other concentrations, possibly via increased activation of astrocytes in hippocampus	[34]
Clinical/epidemiological studies. Retrospective study of suicidal patients	Accidental intake of different Ns	Ns: Imidacloprid	Different concentrations. Single dose	Disorientation, altered mental status, lack of coordination and confusion	[79]

¹mean ± SD.

OCs: Organochlorines; OPs: Organophosphates; NA: Not available; DFP: Diisopropyl fluorophosphate; MMSE: Mini Mental State Examination; CASI: Cognitive Abilities Screening Instrument; Ps: Pyrethroids; Ns: Neonicotinoids; Cs: Carbamates; MCD: Major cognitive disorders; hiPSC: Human-induced pluripotent stem cells; δ-HCH: δ-hexachlorocyclohexane; DDT: Dichlorodiphenyltrichloroethan; AD: Alzheimer’s disease; TCDD: 2,3,7,8 tetrachlorodibenzo-p-dioxin; PD: Parkinson disease.