Agent Orange Causes Metabolic Dysfunction and Molecular Pathology Reminiscent of Alzheimer's Disease

Suzanne M de la Monte; Anuva Goel; Ming Tong; Busra Delikkaya

doi:10.3233/ADR-230046

Agent Orange Causes Metabolic Dysfunction and Molecular Pathology Reminiscent of Alzheimer's Disease

J Alzheimers Dis Rep. 2023 Jul 20;7(1):751-766. doi: 10.3233/ADR-230046. eCollection 2023.

Authors

Suzanne M de la Monte^{1

2

3}, Anuva Goel⁴, Ming Tong², Busra Delikkaya¹

Affiliations

¹ Department of Pathology and Laboratory Medicine, Rhode Island Hospital, Lifespan Academic Institutions, and the Warren Alpert Medical School of Brown University, Providence, RI, USA.
² Department of Medicine, Rhode Island Hospital, Lifespan Academic Institutions, and The Warren Alpert Medical School of Brown University, Providence, RI, USA.
³ Department of Neurology and Neurosurgery, Rhode Island Hospital, Lifespan Academic Institutions, and The Warren Alpert Medical School of Brown University, Providence, RI, USA.
⁴ Department of Neuroscience, Brown University, Providence, RI, USA.

Abstract

Background: Agent Orange, an herbicide used during the Vietnam War, contains 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Agent Orange has teratogenic and carcinogenic effects, and population-based studies suggest Agent Orange exposures lead to higher rates of toxic and degenerative pathologies in the peripheral and central nervous system (CNS).

Objective: This study examines the potential contribution of Agent Orange exposures to neurodegeneration.

Methods: Human CNS-derived neuroepithelial cells (PNET2) treated with 2,4-D and 2,4,5-T were evaluated for viability, mitochondrial function, and Alzheimer's disease (AD)-related proteins.

Results: Treatment with 250μg/ml 2,4-D or 2,4,5-T significantly impaired mitochondrial function, caused degenerative morphological changes, and reduced viability in PNET2 cells. Correspondingly, glyceraldehyde-3-phosphate dehydrogenase expression which is insulin-regulated and marks the integrity of carbohydrate metabolism, was significantly inhibited while 4-hydroxy-2-nonenal, a marker of lipid peroxidation, was increased. Tau neuronal cytoskeletal protein was significantly reduced by 2,4,5-T, and relative tau phosphorylation was progressively elevated by 2,4,5-T followed by 2,4-D treatment relative to control. Amyloid-β protein precursor (AβPP) was increased by 2,4,5-T and 2,4-D, and 2,4,5-T caused a statistical trend (0.05 < p<0.10) increase in Aβ. Finally, altered cholinergic function due to 2,4,5-T and 2,4-D exposures was marked by significantly increased choline acetyltransferase and decreased acetylcholinesterase expression, corresponding with responses in early-stage AD.

Conclusion: Exposures to Agent Orange herbicidal chemicals rapidly damage CNS neurons, initiating a path toward AD-type neurodegeneration. Additional research is needed to understand the permanency of these neuropathologic processes and the added risks of developing AD in Agent Orange-exposed aging Vietnam Veterans.

Keywords: 2; 4; 4-D; 5-T; Agent Orange; Alzheimer’s disease; Veterans; Vietnam; herbicide; neurodegeneration; neurons; pesticide.

Abstract

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