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Environmental Toxins and Alzheimer’s Disease: a Comprehensive Analysis of Pathogenic Mechanisms and Therapeutic Modulation

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Abstract

Alzheimer’s disease is a leading cause of mortality worldwide. Inorganic and organic hazards, susceptibility to harmful metals, pesticides, agrochemicals, and air pollution are major environmental concerns. As merely 5% of AD cases are directly inherited indicating that these environmental factors play a major role in disease development. Long-term exposure to environmental toxins is believed to progress neuropathology, which leads to the development of AD. Numerous in-vitro and in-vivo studies have suggested the harmful impact of environmental toxins at cellular and molecular level. Common mechanisms involved in the toxicity of these environmental pollutants include oxidative stress, neuroinflammation, mitochondrial dysfunction, abnormal tau, and APP processing. Increased expression of GSK-3β, BACE-1, TNF-α, and pro-apoptotic molecules like caspases is observed upon exposure to these environmental toxins. In addition, the expression of neurotrophins like BDNF and GAP-43 have been found to be reduced as a result of toxicity. Further, modulation of signaling pathways involving PARP-1, PGC-1α, and MAPK/ERK induced by toxins have been reported to contribute in AD pathogenesis. These pathways are a promising target for developing novel AD therapeutics. Drugs like epigallocatechin-gallate, neflamapimod, salsalate, dexmedetomidine, and atabecestat are in different phases of clinical trials targeting the pathways for possible treatment of AD. This review aims to culminate the correlation between environmental toxicants and AD development. We emphasized upon the signaling pathways involved in the progression of the disease and the therapeutics under clinical trial targeting the altered pathways for possible treatment of AD.

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Funding

D. H. K. R. received research support from the UGC-BSR (No. F.30–583/2021(BSR) and Central University of Punjab, Bathinda—Research Seed Money (CUPB/CC/PF/20/226). R. D. is the recipient of research fellowship from the Department of Science and Technology—DST-INSPIRE (Reg. No. IF210098), P. S. is the recipient of non-NET fellowship (Ref. No. CUPB/Acad.-54/2022–23/Notification/2472) from Central University of Punjab, and S. K. is the recipient of fellowship AICTE.

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  1. Advanced Pharmacology and Neuroscience Laboratory, Department of Pharmacology, Central University of Punjab, Bathinda, 151 401, India

    Rishika Dhapola, Prajjwal Sharma, Sneha Kumari & Dibbanti HariKrishnaReddy

  2. Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151 401, India

    Jasvinder Singh Bhatti

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  1. Rishika Dhapola
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D. H. K. R. designed the manuscript. R. D., P. S., and S. K. drafted the manuscript. D. H. R. and J. S. B. revised the manuscript for important intellectual content. R. D. and P. S. prepared the illustrated figures. R. D. and S. K. prepared the tables. All authors read and approved the final manuscript. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

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Dhapola, R., Sharma, P., Kumari, S. et al. Environmental Toxins and Alzheimer’s Disease: a Comprehensive Analysis of Pathogenic Mechanisms and Therapeutic Modulation. Mol Neurobiol (2023). https://doi.org/10.1007/s12035-023-03805-x

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