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S100B protects LAN‐5 neuroblastoma cells against Aβ amyloid‐induced neurotoxicity via RAGE engagement at low doses but increases Aβ amyloid neurotoxicity at high doses
Author(s) -
Businaro R.,
Leone S.,
Fabrizi C.,
Sorci G.,
Donato R.,
Lauro G.M.,
Fumagalli L.
Publication year - 2006
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20785
Subject(s) - neurotoxicity , rage (emotion) , neuroprotection , tunel assay , chemistry , pharmacology , programmed cell death , apoptosis , microbiology and biotechnology , toxicity , biology , biochemistry , neuroscience , organic chemistry
Abstract At the concentrations normally found in the brain extracellular space the glial‐derived protein, S100B, protects neurons against neurotoxic agents by interacting with the receptor for advanced glycation end products (RAGE). It is known that at relatively high concentrations S100B is neurotoxic causing neuronal death via excessive stimulation of RAGE. S100B is detected within senile plaques in Alzheimer's disease, where its role is unknown. The present study was undertaken to evaluate a putative neuroprotective role of S100B against Aβ amyloid‐induced neurotoxicity. We treated LAN‐5 neuroblastoma cultures with toxic amounts of Aβ25‐35 amyloid peptide. Our results show that at nanomolar concentrations S100B protects cells against Aβ‐mediated cytotoxicity, as assessed by 3‐(4,5‐dimethyl‐thiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) and terminal deoxynucleotidyl transferase‐mediated dUTP‐fluorescein isothiocyanate nick end‐labeling (TUNEL) experiments, by countering the Aβ‐mediated decrease in the expression of the anti‐apoptotic factor Bcl‐2. This effect depends on S100B binding to RAGE because S100B is unable to contrast Aβ‐mediated neurotoxicity in neurons overexpressing a signaling‐deficient RAGE mutant lacking the cytosolic and transducing domain. Our data suggest that at nanomolar doses S100B counteracts Aβ peptide neurotoxicity in a RAGE‐mediated manner. However, at micromolar doses S100B is toxic to LAN‐5 cells and its toxicity adds to that of the Aβ peptide, suggesting that additional molecular mechanisms may be involved in the neurotoxic process. © 2006 Wiley‐Liss, Inc.