title: Improved Neuroprotection Provided by Drug Combination in Neurons Exposed to Cell-Derived Soluble Amyloid-β Peptide.
abstract: Oligomeric amyloid-β (Aβ) peptide contributes to impaired synaptic connections and neurodegenerative processes, and as such, represents a primary therapeutic target for Alzheimer's disease (AD)-modifying approaches. However, the lack of efficacy of drugs that inhibit production of Aβ demonstrates the need for a better characterization of its toxic effects, both on synaptic and neuronal function. Here, we used conditioned medium obtained from recombinant HEK-AβPP cells expressing the human amyloid-β protein precursor (Aβ-CM), to investigate Aβ-induced neurotoxic and synaptotoxic effects. Characterization of Aβ-CM revealed that it contained picomolar amounts of cell-secreted Aβ in its soluble form. Incubation of primary cortical neurons with Aβ-CM led to significant decreases in synaptic protein levels as compared to controls. This effect was no longer observed in neurons incubated with conditioned medium obtained from HEK-AβPP cells grown in presence of the γ-secretase inhibitor, Semagacestat or LY450139 (LY-CM). However, neurotoxic and pro-apoptotic effects of Aβ-CM were only partially prevented using LY-CM, which could be explained by other deleterious compounds related to chronic oxidative stress that were released by HEK-AβPP cells. Indeed, full neuroprotection was observed in cells exposed to LY-CM by additional treatment with the antioxidant resveratrol, or with the pluripotent n-3 polyunsaturated fatty acid docosahexaenoic acid. Inhibition of Aβ production appeared necessary but insufficient to prevent neurodegenerative effects associated with AD due to other neurotoxic compounds that could exert additional deleterious effects on neuronal function and survival. Therefore, association of various types of protective agents needs to be considered when developing strategies for AD treatment.
authors.affiliation: Université de Lorraine, ENSAIA, UR AFPA, EA 3998, USC INRA 0340, Nancy, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Colin
authors.affiliation: Université de Lorraine, ENSAIA, UR AFPA, EA 3998, USC INRA 0340, Nancy, France.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Allouche
authors.affiliation: Université de Lyon 1, Lyon Neuroscience Research Center; CNRS UMR5292; INSERM U1028; Lyon, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Chauveau
authors.affiliation: Université de Lorraine, ENSAIA, UR AFPA, EA 3998, USC INRA 0340, Nancy, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Corbier
authors.affiliation: Université de Lorraine, ENSAIA, UR AFPA, EA 3998, USC INRA 0340, Nancy, France.
authors.forename: Lynn
authors.initials: L
authors.lastname: Pauron-Gregory
authors.affiliation: Université de Lorraine, ENSAIA, UR AFPA, EA 3998, USC INRA 0340, Nancy, France.
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Lanhers
authors.affiliation: Université de Lorraine, ENSAIA, UR AFPA, EA 3998, USC INRA 0340, Nancy, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Claudepierre
authors.affiliation: Université de Lorraine, ENSAIA, UR AFPA, EA 3998, USC INRA 0340, Nancy, France.
authors.forename: Frances T
authors.initials: FT
authors.lastname: Yen
authors.affiliation: Université de Lorraine, ENSAIA, UR AFPA, EA 3998, USC INRA 0340, Nancy, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Oster
authors.affiliation: Université de Lorraine, ENSAIA, UR AFPA, EA 3998, USC INRA 0340, Nancy, France.|Laboratoire de Biochimie, Hôpital Central, CHU de Nancy, CO n°34, Nancy, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Malaplate-Armand
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004622:Embryo, Mammalian; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001381:Azepines; D017077:Culture Media, Conditioned; D005904:Glial Fibrillary Acidic Protein; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D018696:Neuroprotective Agents; D053148:Caspase 3; D010751:Phosphopyruvate Hydratase; D000409:Alanine
keywords: Alzheimer’s disease; cell-generated Aβ peptide; neuronal apoptosis; neuroprotection; oxidative stress; synaptic proteins