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

Abstract

Alzheimer's disease (AD) is a progressive and neurodegenerative illness which results in alterations in cognitive development. It is characterized by loss/dysfunction of cholinergic neurons, and formation of amyloid plaques, and formation of neurofibrillary tangles, among other changes, due to hyperphosphorylation of tau-protein. Exposure to pesticides in humans occurs frequently due to contact with contaminated food, water, or particles. Organochlorines, organophosphates, carbamates, pyrethroids and neonicotinoids are associated with the most diagnosed incidents of severe cognitive impairment. The aim of this study was to determine the effects of these pesticides on the phosphorylation of tau protein, and its cognitive implications in the development of AD. It was found that exposure to pesticides increased the phosphorylation of tau protein at sites Ser198, Ser199, Ser202, Thr205, Ser396 and Ser404. Contact with these chemicals altered the enzymatic activities of cyclin-dependent kinase 5 and glycogen synthase kinase 3 beta, and protein phosphatase-2A. Moreover, it altered the expression of the microtubule associated protein tau gene, and changed levels of intracellular calcium. These changes affected tau protein phosphorylation and neuroinflammation, and also increased oxidative stress. In addition, the exposed subjects had poor level of performance in tests that involved evaluation of novelty, as test on verbal, non-verbal, spatial memory, attention, and problem-solving skills.

Keywords: Carbamates; Neonicotinoids; Organochlorines; Organophosphates; Pyrethroids; Tau protein.

Figure 1

Pesticide effect on phosphorylation in tau. Exposure to pesticides organochlorine, organophosphate, carbamate, pyrethroid and neonicotinoid alters the balance of enzymatic activity of glycogen synthase kinase 3 beta (GSK-3β) and protein phosphatase-2A (PP2A). Especially the increase of GSK-3β and the decrease of PP2A favors tau hyperphosphorylation and the formation of neurofibrillary tangle which induce the activation of microglia and neuroinflammations. Created with Biorender.com. OCs: Organochlorine; OPs: Organophosphate; Cs: Carbamate; Ps: Pyrethroid; Ns: Neonicotinoid; GSK-3β: Glycogen synthase kinase 3 beta; PP2A: Protein phosphatase-2A; TNF: Tumor necrosis factor; IL: Interleukin.