Tiziana Petrozziello1, Alexandra N Mills1, Sali M K Farhan2,3, Kaly A Mueller1, Eric J Granucci1, Kelly E Glajch1, James Chan4, Sheena Chew1, James D Berry1, Ghazaleh Sadri-Vakili1. 1. Sean M. Healey & AMG Center for ALS at Mass General, Massachusetts General Hospital, Boston, Massachusetts. 2. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. 3. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts. 4. Biostatistics Center, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Abstract
BACKGROUND: The exact mechanisms underlying neuroinflammation and how they contribute to amyotrophic lateral sclerosis (ALS) pathogenesis remain unclear. One possibility is the secretion of neurotoxic factors, such as lipocalin-2 (LCN2), that lead to neuronal death. METHODS: LCN2 levels were measured in human postmortem tissue using Western blot, quantitative real time polymerase chain reaction, and immunofluorescence, and in plasma by enzyme-linked immunosorbent assay. SH-SY5Y cells were used to test the pro-inflammatory effects of LCN2. RESULTS: LCN2 is increased in ALS postmortem motor cortex, spinal cord, and plasma. Furthermore, we identified several LCN2 variants in ALS patients that may contribute to disease pathogenesis. Lastly, while LCN2 treatment caused cell death and increased pro-inflammatory markers, treatment with an anti-LCN2 antibody prevented these responses in vitro. CONCLUSIONS: LCN2 upregulation in ALS postmortem samples and plasma may be an upstream event for triggering neuroinflammation and neuronal death.
BACKGROUND: The exact mechanisms underlying neuroinflammation and how they contribute to amyotrophic lateral sclerosis (ALS) pathogenesis remain unclear. One possibility is the secretion of neurotoxic factors, such as lipocalin-2 (LCN2), that lead to neuronal death. METHODS:LCN2 levels were measured in human postmortem tissue using Western blot, quantitative real time polymerase chain reaction, and immunofluorescence, and in plasma by enzyme-linked immunosorbent assay. SH-SY5Y cells were used to test the pro-inflammatory effects of LCN2. RESULTS:LCN2 is increased in ALS postmortem motor cortex, spinal cord, and plasma. Furthermore, we identified several LCN2 variants in ALSpatients that may contribute to disease pathogenesis. Lastly, while LCN2 treatment caused cell death and increased pro-inflammatory markers, treatment with an anti-LCN2 antibody prevented these responses in vitro. CONCLUSIONS:LCN2 upregulation in ALS postmortem samples and plasma may be an upstream event for triggering neuroinflammation and neuronal death.
Authors: Tiziana Petrozziello; Ana C Amaral; Simon Dujardin; Sali M K Farhan; James Chan; Bianca A Trombetta; Pia Kivisäkk; Alexandra N Mills; Evan A Bordt; Spencer E Kim; Patrick M Dooley; Caitlin Commins; Theresa R Connors; Derek H Oakley; Anubrata Ghosal; Teresa Gomez-Isla; Bradley T Hyman; Steven E Arnold; Tara Spires-Jones; Merit E Cudkowicz; James D Berry; Ghazaleh Sadri-Vakili Journal: Brain Pathol Date: 2021-11-14 Impact factor: 6.508