Glyphosate Infiltrates the Brain: Neurological Outcomes and Neurodegenerative Implications

Glyphosate is the most heavily used herbicide worldwide and recent reports indicate that it may have deleterious neurological and neurodegenerative effects on human health. Here I demonstrate that glyphosate can infiltrate the brain in a dose-dependent manner in mice sub-acutely exposed to 125, 250, or 500 mg/kg/day. I also establish that glyphosate elicits a neuroinflammatory response in both the cortex and hippocampus, marked by elevation of tumor necrosis factor α (TNFα), and causes transcriptomic dysregulation of key genes involved in oligodendrocyte proliferation, maturation, and myelination. Given that both the hippocampus and the cortex are critical for learning and memory, and are affected in Alzheimer’s disease (AD), I investigate how 50 or 500 mg/kg chronic glyphosate exposure influences locomotion, anxiety-like behavior, and cognition in the APP/PS1 mouse model of AD. Results show that while glyphosate did not influence weight, appearance, locomotion, or anxiety-like behavior, learning acquisition is impaired in the place preference and reaction time tasks following 500mg/kg chronic exposure. Additionally, I report a strong increase in water consumption in glyphosate-exposed mice, demonstrating that chronic glyphosate exposure induces polydipsia. To ascertain whether glyphosate influences AD pathogenesis, I examine neuropathological changes following chronic daily oral exposure to 50 or 500 mg/kg glyphosate. Post-mortem analysis of amyloid-beta (Aβ) in APP/PS1 hippocampal and cortical tissue show that 50 or 500 mg/kg of glyphosate elevates soluble and insoluble Aβ1-40 and Aβ1-42 in both sexes, with females showing higher levels. Further analysis of cortical TNFα levels in chronically exposed APP/PS1 mice and littermate controls confirms a neuroinflammatory response. I report no differences in amyloid precursor protein (APP) processing pathway components, CA1 NeuN+ neuronal number, relative density of Iba1+ microglia in the hippocampus, or relative density of MBP+ oligodendrocytes in the fimbria. I also show that 50mg/kg chronic glyphosate exposure elevates hemoglobin A1c levels, indicating disruptions in glucose metabolism that may be tied to polydipsia. Collectively, these results indicate that glyphosate crosses the blood-brain barrier, induces a neuroinflammatory response, and exacerbates amyloid pathology. Ultimately, these findings provide important insight into the concerns surrounding the neurological implications of glyphosate exposure.