EC Neurology

Diseases like Alzheimer’s and Parkinson’s are associated with the aggregation of amyloids. Scientists have learnt that besides natural speed bumps such as the ageing process and genes, a greater role is played by environmental toxins. Hazardous substances like lead, mercury and aluminum, among others, have the ability to disrupt the protein homeostasis through the induction of oxidative stress, proteasomal blockage, and alteration of mitochondrial electrical activity. By enhancing the misfolding of amyloid-β, α-synuclein and tau proteins along with their aggregation, these disruptions lead to synaptic dysfunction and neuronal loss. Exposure to the environment can worsen the risk and severity of the genetic predisposition to disease. Experimental studies in cell and animal models have shown that chronic exposure to toxins enhances the deposition of amyloid and intensifies neuroinflammation. Epidemiological studies have linked environmental risk factors to amyloid-related neurodegenerative disease. While much of this was observed in transgenic mice, findings were seen in wild-type animals as well and mainly involved the Aβ42 peptide. Examining how environmental toxins and amyloid clumping interact can help develop better ways to prevent neurodegenerative disease and assess the risk, along with new therapies.

 Keywords: Amyloid Aggregation; Environmental Toxins; Neurodegeneration; Oxidative Stress; Protein Misfolding

1. Yang M. “The effect of posttranslational modifications on protein aggregation, morphology, and toxicity”. (2016).
2. Ezzat K., et al. “Proteins do not replicate, they precipitate: Phase transition and loss of function toxicity in amyloid pathologies”. Biology 4 (2022).
3. Nabi M and Tabassum N. “Role of environmental toxicants on neurodegenerative disorders”. Frontiers in Toxicology 4 (2022): 837579.
4. Willbold D., et al. “Amyloid-type protein aggregation and prion-like properties of amyloids”. Chemical Reviews13 (2021): 8285-8307.
5. Su H., et al. “Amyloid‐like protein aggregation toward pesticide reduction”. Advanced Science13 (2022): e2105106.
6. Sinnige T. “Molecular mechanisms of amyloid formation in living systems”. Chemical Science24 (2022): 7080-7097.
7. Giorgetti S., et al. “Targeting amyloid aggregation: An overview of strategies and mechanisms”. International Journal of Molecular Sciences 9 (2018): 2677.
8. Wu YC., et al. “The contribution of β-amyloid, Tau and α-synuclein to blood–brain barrier damage in neurodegenerative disorders”. Acta Neuropathologica1 (2024): 39.
9. Ricci C. “Neurodegenerative disease: from molecular basis to therapy”. International Journal of Molecular Sciences2 (2024): 967.
10. Acquasaliente L and De Filippis V. “The role of proteolysis in amyloidosis”. International Journal of Molecular Sciences1 (2022): 699.
11. Galkin AP and Sysoev EI. “Stress response is the main trigger of sporadic amyloidosis”. International Journal of Molecular Sciences8 (2021): 4092.
12. Cascella R., et al. “Effects of oligomer toxicity, fibril toxicity and fibril spreading in synucleinopathies”. Cellular and Molecular Life Sciences3 (2022): 174.
13. Limbocker R., et al. “Characterization of pairs of toxic and nontoxic misfolded protein oligomers elucidates the structural determinants of oligomer toxicity in protein misfolding diseases”. Accounts of Chemical Research12 (2023): 1395-1405.
14. Madhu P and Mukhopadhyay S. “Distinct types of amyloid‐β oligomers displaying diverse neurotoxicity mechanisms in Alzheimer's disease”. Journal of Cellular Biochemistry11 (2021): 1594-1608.
15. Forloni G. “Oligomers and neurodegeneration: new evidence”. Aging and Disease6 (2023): 1977-1980.
16. Tolar M., et al. “Neurotoxic soluble amyloid oligomers drive Alzheimer’s pathogenesis and represent a clinically validated target for slowing disease progression”. International Journal of Molecular Sciences12 (2021): 6355.
17. Ma C., et al. “Amyloidosis in Alzheimer's disease: Pathogeny, etiology, and related therapeutic directions”. Molecules4 (2022): 1210.
18. Talar-Wojnarowska R. “Intestinal amyloidosis: clinical manifestations and diagnostic challenge”. Advances in Clinical and Experimental Medicine5 (2021): 563-570.
19. Sciaccaluga M., et al. “An unbalanced synaptic transmission: cause or consequence of the amyloid oligomers neurotoxicity?”. International Journal of Molecular Sciences 11 (2021): 5991.
20. Gonzalez-Garcia M., et al. “Membrane interactions and toxicity by misfolded protein oligomers”. Frontiers in Cell and Developmental Biology 9 (2021): 642623.
21. Lobine D., et al. “Potential of medicinal plants as neuroprotective and therapeutic properties against amyloid-β-related toxicity, and glutamate-induced excitotoxicity in human neural cells”. Current Neuropharmacology 9 (2021): 1416-1441.
22. Pinky PD., et al. “Recent insights on glutamatergic dysfunction in Alzheimer’s disease and therapeutic implications”. The Neuroscientist4 (2023): 461-471.
23. Yang Z., et al. “Neurotransmitters in prevention and treatment of Alzheimer's disease”. International Journal of Molecular Sciences4 (2023): 3841.
24. Arriagada J., et al. “Excitatory-inhibitory synaptic imbalance induced by acute intra-hippocampus injections of amyloid-β oligomers”. Biochemical and Biophysical Research Communications 742 (2025): 151133.
25. Golmohammadi M., et al. “Neuroprotective effects of riluzole in Alzheimer's disease: A comprehensive review”. Fundamental and Clinical Pharmacology2 (2024): 225-237.
26. Satarker S., et al. “Astrocytic glutamatergic transmission and its implications in neurodegenerative disorders”. Cells 7 (2022): 1139.
27. Yadav B., et al. “Implications of organophosphate pesticides on brain cells and their contribution toward progression of Alzheimer's disease”. Journal of Biochemical and Molecular Toxicology 3 (2024): e23660.
28. Ruiz-Arias Álvaro M., et al. “Seeding and growth of β-amyloid aggregates upon interaction with neuronal cell membranes”. International Journal of Molecular Sciences 4 (2020): 5035.
29. Candelise N., et al. “Protein aggregation landscape in neurodegenerative diseases: Clinical relevance and future applications”. International Journal of Molecular Sciences11 (2021): 6016.
30. Bhattacharya S and Thompson D. “Recent advances in mapping protein self-assembly and aggregation for common proteinopathies”. Acta Physica Polonica A 3 (2024).
31. Basak A and Basak S. “Protein aggregation and self assembly in health and disease”. Current Proteomics1 (2022): 4-19.
32. Chen H., et al. “Surface-directed structural transition of amyloidogenic aggregates and the resulting neurotoxicity”. ACS Omega 6 (2020): 2856-2864.
33. Dhapola R., et al. “Environmental toxins and Alzheimer’s disease: a comprehensive analysis of pathogenic mechanisms and therapeutic modulation”. Molecular Neurobiology6 (2024): 3657-3677.
34. Yakupova EI., et al. “Amyloids: the history of toxicity and functionality”. Biology5 (2021): 394.
35. J Tamás M., et al. “Heavy metals and metalloids as a cause for protein misfolding and aggregation”. Biomolecules 1 (2014): 252-267.
36. Kumar P. “Heavy metal contamination causes protein misfolding, leading to neurodegenerative disorders”. Protein Misfolding in Neurodegenerative Diseases (2025): 463-492.
37. Kumar P. “Intersections of heavy metal toxicity, protein misfolding, and neurodegenerative disorders in humans”. Protein Misfolding in Neurodegenerative Diseases (2025): 413-461.
38. Murumulla L., et al. “Heavy metal mediated progressive degeneration and its noxious effects on brain microenvironment”. Biological Trace Element Research4 (2024): 1411-1427.
39. Huang M., et al. “Impact of environmental risk factors on mitochondrial dysfunction, neuroinflammation, protein misfolding, and oxidative stress in the etiopathogenesis of Parkinson’s disease”. International Journal of Molecular Sciences 18 (2022): 10808.
40. Luen Tang B. “Neuropathological mechanisms associated with pesticides in Alzheimer’s disease”. Toxics2 (2020): 21.
41. Rodríguez A., et al. “Pesticides: Environmental stressors implicated in the development of central nervous system disorders and neurodegeneration”. Stresses2 (2025): 31.
42. Trevisan K., et al. “The indiscriminate use of pesticides could increase the prevalence of Alzheimer's disease? a systematic review”. International Neuropsychiatric Disease Journal 4 (2024): 47-60.
43. D'Souza LC., et al. “Environmental chemical-induced reactive oxygen species generation and immunotoxicity: a comprehensive review”. Antioxidants and Redox Signaling10-12 (2024): 691-714.
44. Liu J., et al. “Reactive oxygen species (ROS) scavenging biomaterials for anti-inflammatory diseases: from mechanism to therapy”. Journal of Hematology and Oncology1 (2023): 116.
45. Zhang C., et al. “Reactive oxygen species‐regulating strategies based on nanomaterials for disease treatment”. Advanced Science3 (2021): 2002797.
46. Johnson P. “Effect of volatile organic compounds on the neurobehavioral functions of painters in Chennai, Tamilnadu: A cross sectional study”. National Journal of Community Medicine 10 (2023): 658-665.
47. Moura PC., et al. “Towards the identification of the volatile organic compounds emitted by the coatings used in a car factory painting line”. Journal of Coatings Technology and Research2 (2024): 665-682.
48. Hasylin H., et al. “A preliminary assessment of health and safety in the automobile industry in Brunei Darussalam: workers’ knowledge and practice of organic solvents”. International Journal of Environmental Research and Public Health23 (2022): 15469.
49. Hasylin H., et al. “Knowledge and practice of health and safety in handling organic solvents among automobile industry workers in Brunei Darussalam”.
50. Pilon L., et al. “Development of a solvent sustainability guide for the paints and coatings industry”. Green Chemistry18 (2024): 9697-9711.
51. Ajmal MR. “Protein misfolding and aggregation in proteinopathies: causes, mechanism and cellular response”. Diseases1 (2023): 30.
52. Louros N., et al. “Mechanisms and pathology of protein misfolding and aggregation”. Nature Reviews Molecular Cell Biology12 (2023): 912-933.
53. Ahanger IA., et al. “Comprehensive perspective towards the management of proteinopathies by elucidating protein misfolding and aggregation”. CNS and Neurological Disorders-Drug Targets2 (2024): 153-180.
54. Ochneva A., et al. “Protein misfolding and aggregation in the brain: common pathogenetic pathways in neurodegenerative and mental disorders”. International Journal of Molecular Sciences22 (2022): 14498.
55. Bai Y., et al. “Advanced techniques for detecting protein misfolding and aggregation in cellular environments”. Chemical Reviews21 (2023): 12254-12311.
56. Feitosa VA., et al. “Renal amyloidosis: a new time for a complete diagnosis”. Brazilian Journal of Medical and Biological Research 55 (2022): e12284.
57. Radbakhsh S., et al. “Curcumin: A small molecule with big functionality against amyloid aggregation in neurodegenerative diseases and type 2 diabetes”. Biofactors 4 (2021): 570-586.
58. Rani N., et al. “Toxicity of Glyphosate accelerates neurodegeneration in Caenorhabditis elegans model of Alzheimer's Disease”. Frontiers in Toxicology 7 (2025): 1578230.
59. Morel B., et al. “Rapid conversion of amyloid-beta 1-40 oligomers to mature fibrils through a self-catalytic bimolecular process”. International Journal of Molecular Sciences 12 (2021): 6370.
60. Li J and Deepak FL. “In situ kinetic observations on crystal nucleation and growth”. Chemical Reviews23 (2022): 16911-16982.
61. Carpenter BP., et al. “Understanding and controlling the nucleation and growth of metal–organic frameworks”. Chemical Society Reviews20 (2023): 6918-6937.
62. Zhang Y., et al. “Inhibition of crystal nucleation and growth: a review”. Crystal Growth and Design6 (2024): 2645-2665.
63. Robles-Fernández A., et al. “The role of microorganisms in the nucleation of carbonates, environmental implications and applications”. Minerals 12 (2022): 1562.
64. Lin J., et al. “Understanding the nanoscale phenomena of nucleation and crystal growth in electrodeposition”. Nanoscale 42 (2024): 19564-19588.
65. Du Z., et al. “Current strategies for modulating Aβ aggregation with multifunctional agents”. Accounts of Chemical Research9 (2021): 2172-2184.
66. Matveyenka M., et al. “Amyloid aggregates exert cell toxicity causing irreversible damages in the endoplasmic reticulum”. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease11 (2022): 166485.
67. Kalsoom I., et al. “Research progress of α-synuclein aggregation inhibitors for potential Parkinson’s disease treatment”. Mini Reviews in Medicinal Chemistry20 (2023): 1959-1974.
68. Gonzalez-Garcia M., et al. “Membrane interactions and toxicity by misfolded protein oligomers”. Frontiers in Cell and Developmental Biology 9 (2021): 642623.
69. Lindell AE., et al. “Multimodal interactions of drugs, natural compounds and pollutants with the gut microbiota”. Nature Reviews Microbiology7 (2022): 431-443.
70. Sawaya MR., et al. “The expanding amyloid family: Structure, stability, function, and pathogenesis”. Cell 19 (2021): 4857-4873.
71. L Almeida Z and MM Brito R. “Structure and aggregation mechanisms in amyloids”. Molecules 5 (2020): 1195.
72. Yu Y., et al. “Amyloid‐β in Alzheimer's disease: Structure, toxicity, distribution, treatment, and prospects”. ibrain3 (2024): 266-289.
73. Gou X., et al. “Impact of nanoplastics on Alzheimer’s disease: Enhanced amyloid-β peptide aggregation and augmented neurotoxicity”. Journal of Hazardous Materials 465 (2024): 133518.
74. N Minniti A., et al. “Intracellular amyloid formation in muscle cells of Aβ-transgenic Caenorhabditis elegans: determinants and physiological role in copper detoxification”. Molecular Neurodegeneration 4 (2009): 2.