Glyphosate use in the United States (US) has increased each year since the introduction of glyphosate-tolerant crops in 1996, yet little is known about its effects on the brain. We recently found that Show more
Glyphosate use in the United States (US) has increased each year since the introduction of glyphosate-tolerant crops in 1996, yet little is known about its effects on the brain. We recently found that C57BL/6J mice dosed with glyphosate for 14 days showed glyphosate and its major metabolite aminomethylphosphonic acid present in brain tissue, with corresponding increases in pro-inflammatory cytokine tumor necrosis factor-⍺ (TNF-⍺) in the brain and peripheral blood plasma. Since TNF-⍺ is elevated in neurodegenerative disorders such as Alzheimer's Disease (AD), in this study, we asked whether glyphosate exposure serves as an accelerant of AD pathogenesis. Additionally, whether glyphosate and aminomethylphosphonic acid remain in the brain after a recovery period has yet to be examined. We hypothesized that glyphosate exposure would induce neuroinflammation in control mice, while exacerbating neuroinflammation in AD mice, causing elevated Amyloid-β and tau pathology and worsening spatial cognition after recovery. We dosed 4.5-month-old 3xTg-AD and non-transgenic (NonTg) control mice with either 0, 50 or 500 mg/kg of glyphosate daily for 13 weeks followed by a 6-month recovery period. We found that aminomethylphosphonic acid was detectable in the brains of 3xTg-AD and NonTg glyphosate-dosed mice despite the 6-month recovery. Glyphosate-dosed 3xTg-AD mice showed reduced survival, increased thigmotaxia in the Morris water maze, significant increases in the beta secretase enzyme (BACE-1) of amyloidogenic processing, amyloid-β (Aβ) 42 insoluble fractions, Aβ 42 plaque load and plaque size, and phosphorylated tau (pTau) at epitopes Threonine 181, Serine 396, and AT8 (Serine 202, Threonine 205). Notably, we found increased pro- and anti-inflammatory cytokines and chemokines persisting in both 3xTg-AD and NonTg brain tissue and in 3xTg-AD peripheral blood plasma. Taken together, our results are the first to demonstrate that despite an extended recovery period, exposure to glyphosate elicits long-lasting pathological consequences. As glyphosate use continues to rise, more research is needed to elucidate the impact of this herbicide and its metabolites on the human brain, and their potential to contribute to dysfunctions observed in neurodegenerative diseases. Show less
Cholesterol dysregulation has been implicated in age-related macular degeneration (AMD), the most common cause of visual impairment in the elderly. The 18 KDa translocator protein (TSPO) is a mitochon Show more
Cholesterol dysregulation has been implicated in age-related macular degeneration (AMD), the most common cause of visual impairment in the elderly. The 18 KDa translocator protein (TSPO) is a mitochondrial outer membrane protein responsible for transporting cholesterol from the mitochondrial outer membrane to the inner membrane. TSPO is highly expressed in retinal pigment epithelial (RPE) cells, and TSPO ligands have shown therapeutic potential for the treatment of AMD. Here, we characterized retinal pathology of Show less
Citrulline is among the metabolites measured by expanded newborn screening (NBS). While hypocitrullinemia can be a marker for deficiency of proximal urea cycle enzymes such as ornithine transcarbamyla Show more
Citrulline is among the metabolites measured by expanded newborn screening (NBS). While hypocitrullinemia can be a marker for deficiency of proximal urea cycle enzymes such as ornithine transcarbamylase (OTC), only a handful of state newborn screening programs in the United States officially report a low citrulline value for further work-up due to low positive predictive value. We report a case of a male infant who was found to have hypocitrullinemia on NBS. After excluding proximal urea cycle disorders by DNA sequencing, his NBS result was felt to be a false positive. At 4 months of age, he developed poor feeding, failure to thrive, apnea and infantile spasms with a progression to intractable seizures, as well as persistent hypocitrullinemia. He was diagnosed with Leigh syndrome due to a maternally inherited homoplasmic m.8993T>G mutation in the ATPase 6 gene. His mother, who had previously been diagnosed with cerebral palsy, was concurrently diagnosed with neuropathy, ataxia, and retinitis pigmentosa (NARP) due to heteroplasmy of the same mutation. She had progressive muscle weakness, ataxia, and speech dyspraxia. The m.8993T>G mutation causes mitochondrial ATP synthase deficiency and it is hypothesized to undermine the synthesis of citrulline by CPS1. In addition to proximal urea cycle disorders, the evaluation of an infant with persistent hypocitrullinemia should include testing for the m.8993T>G mutation and other disorders that cause mitochondrial dysfunction. Show less