l-Serine Reduces Spinal Cord Pathology in a Vervet Model of Preclinical ALS/MND.

Abstract

The early neuropathological features of amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) are protein aggregates in motor neurons and microglial activation. Similar pathology characterizes Guamanian ALS/Parkinsonism dementia complex, which may be triggered by the cyanotoxin β-N-methylamino-l-alanine (BMAA). We report here the occurrence of ALS/MND-type pathological changes in vervets (Chlorocebus sabaeus; n = 8) fed oral doses of a dry powder of BMAA HCl salt (210 mg/kg/day) for 140 days. Spinal cords and brains from toxin-exposed vervets were compared to controls fed rice flour (210 mg/kg/day) and to vervets coadministered equal amounts of BMAA and l-serine (210 mg/kg/day). Immunohistochemistry and quantitative image analysis were used to examine markers of ALS/MND and glial activation. UHPLC-MS/MS was used to confirm BMAA exposures in dosed vervets. Motor neuron degeneration was demonstrated in BMAA-dosed vervets by TDP-43+ proteinopathy in anterior horn cells, by reactive astrogliosis, by activated microglia, and by damage to myelinated axons in the lateral corticospinal tracts. Vervets dosed with BMAA + l-serine displayed reduced neuropathological changes. This study demonstrates that chronic dietary exposure to BMAA causes ALS/MND-type pathological changes in the vervet and coadministration of l-serine reduces the amount of reactive gliosis and the number of protein inclusions in motor neurons.

• Authors: David A Davis, Paul Alan Cox, Sandra Anne Banack, Patricia D Lecusay, Susanna P Garamszegi, Matthew J Hagan, James T Powell, James S Metcalf, Roberta M Palmour, Amy Beierschmitt, Walter G Bradley, Deborah C Mash
• Journal: Journal of neuropathology and experimental neurology (J Neuropathol Exp Neurol) Vol. 79 Issue 4 Pg. 393-406 (04 01 2020) ISSN: 1554-6578 [Electronic] England
• PMID: 32077471 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 American Association of Neuropathologists, Inc.

Chemical References

• Amino Acids, Diamino
• Cyanobacteria Toxins
• beta-N-methylamino-L-alanine
• Serine

Topics

• Amino Acids, Diamino (toxicity)
• Amyotrophic Lateral Sclerosis (chemically induced, pathology)
• Animals
• Chlorocebus aethiops
• Cyanobacteria Toxins
• Disease Models, Animal
• Male
• Microglia (drug effects, pathology)
• Motor Neuron Disease (chemically induced, pathology)
• Motor Neurons (drug effects, pathology)
• Pyramidal Tracts (drug effects, pathology)
• Serine (administration & dosage)
• Spinal Cord (drug effects, pathology)