### CHF5074 protects SH-SY5Y human neuronal-like cells from amyloidbeta 25-35 and tumor necrosis factor related apoptosis inducing ligand toxicity in vitro

#### Abstract

Alzheimer's disease (AD) is contributed by multiple pathogenic causes. The anomalous protein amyloid-β (Aβ) is regarded as a pivotal factor in AD, and originates from enzymatic cleavage of a precursor protein by the secretase family. 1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074) is a non-steroidal antiinflammatory derivative able to inhibit Aβ deposition in the brain of transgenic mouse models of AD. The proapoptotic cytokine TRAIL has been reported to mediate Aβ-dependent neurotoxicity. Here, the effects of CHF5074 on Aβ25-35- triggered TRAIL toxicity were evaluated in the differentiated human neuroblastoma cell line SH-SY5Y in vitro. Cells were pre-treated 1h with CHF5074 at graded concentrations (range: 1 nM-1 uM) and then challenged for 72 h with either Aβ25-35 or TRAIL. Results show that CHF5074 treatment prevented apoptotic death in SH-SY5Y cell line in a concentration- dependent fashion. Its maximally active concentration was 10 nM. Then, investigation of related molecular mechanisms underlying such protective effect of CHF5074 suggested that the levels of caspases, as well as of various kinases, including stress and MAP kinases, are modulated by CHF5074. Finally, treatment of injured human neuroblastoma cell line SH-SY5Y with CHF5074 resulted in prominent protection from apoptotic death. The bulk of these data suggest that CHF5074 represents a potential candidate for pharmacological neuroprotective treatment in neurodegenerative disorders. 

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Breve descrizione dei contenuti (Abstract)

_Alzheimer's disease (AD) is contributed by multiple pathogenic causes. The anomalous protein amyloid-β (Aβ) is regarded as a pivotal factor in AD, and originates from enzymatic cleavage of a precursor protein by the secretase family. 1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074) is a non-steroidal antiinflammatory derivative able to inhibit Aβ deposition in the brain of transgenic mouse models of AD. The proapoptotic cytokine TRAIL has been reported to mediate Aβ-dependent neurotoxicity. Here, the effects of CHF5074 on Aβ25-35- triggered TRAIL toxicity were evaluated in the differentiated human neuroblastoma cell line SH-SY5Y in vitro. Cells were pre-treated 1h with CHF5074 at graded concentrations (range: 1 nM-1 uM) and then challenged for 72 h with either Aβ25-35 or TRAIL. Results show that CHF5074 treatment prevented apoptotic death in SH-SY5Y cell line in a concentration- dependent fashion. Its maximally active concentration was 10 nM. Then, investigation of related molecular mechanisms underlying such protective effect of CHF5074 suggested that the levels of caspases, as well as of various kinases, including stress and MAP kinases, are modulated by CHF5074. Finally, treatment of injured human neuroblastoma cell line SH-SY5Y with CHF5074 resulted in prominent protection from apoptotic death. The bulk of these data suggest that CHF5074 represents a potential candidate for pharmacological neuroprotective treatment in neurodegenerative disorders. _