Abstract
Environmental toxicants have been implicated in neurodegenerative diseases, and pesticide exposure is a suspected environmental risk factor for Alzheimer’s disease (AD). Several epidemiological analyses have affirmed a link between pesticides and incidence of sporadic AD. Meanwhile, in vitro and animal models of AD have shed light on potential neuropathological mechanisms. In this paper, a perspective on neuropathological mechanisms underlying pesticides’ induction of AD is provided. Proposed mechanisms range from generic oxidative stress induction in neurons to more AD-specific processes involving amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau). Mechanisms that are more speculative or indirect in nature, including somatic mutation, epigenetic modulation, impairment of adult neurogenesis, and microbiota dysbiosis, are also discussed. Chronic toxicity mechanisms of environmental pesticide exposure crosstalks in complex ways and could potentially be mutually enhancing, thus making the deciphering of simplistic causal relationships difficult.
Highlights
Alzheimer’s disease (AD) [1,2] is the most prevalent cause of age-associated dementia worldwide [3]
Intraneuronal neurofibrillary tangles (IFTs) are enriched in the hyperphosphorylated form of a microtubule-binding protein tau [5], while extracellular amyloid plaques consist of insoluble aggregates of amyloid β (Aβ) peptides generated via proteolytic processing of the amyloid precursor protein (APP) [6]
More recent meta-analysis in 2019 of 19 studies of occupational exposures to multiple agents on neurodegenerative diseases (13 on AD) has concluded that occupational exposure to pesticides increased the risk of AD (weighted relative risk (RR), 95% confidence interval (CI): 1.50, 0.98–2.29) [52]
Summary
Alzheimer’s disease (AD) [1,2] is the most prevalent cause of age-associated dementia worldwide [3]. Postulates that the production of Aβ1-42 (and related peptides) with the subsequent formation of amyloid plaques as the etiological origin of AD, while the amyloid-β oligomer hypothesis emphasizes the greater neurotoxicity of soluble Aβ oligomers compared to those within insoluble amyloid plaques [14]. In vivo, both tau and Aβ contribute to AD pathology [14,15] and the development and Toxics 2020, 8, 21; doi:10.3390/toxics8020021 www.mdpi.com/journal/toxics. Information on disease etiology, recently-obtained mechanistic insights from cellular and animal models, is highlighted
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